KR19990082487A - Novel Cefem Compounds and Their Pharmaceutical Uses - Google Patents

Abstract

The present invention relates to a novel cefem compound represented by formula (I) or a salt thereof having an antimicrobial activity against Helicobacter pylori, which is useful as an antihelicobacter pylori, anti gastritis, antiulcer and anticancer agent.

Formula I

In Formula I,

Each symbol is as defined herein.

Description

Novel cefem compounds and pharmaceutical uses thereof

Field of invention

The present invention relates to cephem compounds and pharmaceutically acceptable salts thereof.

In particular, the present invention provides novel cefem compounds and salts thereof having antimicrobial activity against Helicobacter pylori, pharmaceutical compositions comprising the cefem compound or pharmaceutically acceptable salts thereof and the prevention of ulcers in humans or animals. And / or to treat and prevent gastric cancer.

Background

At present, acid secretion inhibitors, and mucosal protective factor reinforcing agents, such as H ₂ blockers and proton pump inhibitors (proton pump inhibitor) is mainly used for the treatment of peptic ulcers such as gastric ulcer and duodenal ulcer. Although the duration of treatment is reduced with the use of H ₂ blockers and quantum pump inhibitors, the problem of possible recurrence of the disease to be solved remains.

Helicobacter pylori (H. pylori) is a Gram negative bacterium found in the mucosal layer above the human epithelium, and when infected with H. pylori, gastrointestinal tracts such as chronic gastritis and peptic ulcers (e.g. gastric ulcer, duodenal ulcer) It has been found to cause disease. There is increasing reports of the effectiveness of the eradication of H. pylori to treat intractable ulcers and prevent recurrence of ulcers. Agents with antimicrobial activity against H. pylori are useful for the treatment and / or prevention of gastritis and ulcers, and novel agents with pharmacological activity are preferred.

Detailed description of the invention

It is an object of the present invention to provide novel cefem compounds and salts thereof having antibacterial activity against Helicobacter pylori .

Cephem compounds and salts thereof are useful as a (anti-Helicobacter pylori agent), anti-gastritis agents, anti-ulcer agents and anticancer agents, wherein H. pylori. Cefem compounds and salts thereof can be usefully used as anti- helicobacter pylori , anti-gastric, anti-ulcer and anticancer agents in combination with acid secretion inhibitors such as H ₂ blockers and proton pump inhibitors.

A further object of the present invention is to provide a pharmaceutical composition comprising the cefem compound or a pharmaceutically acceptable salt thereof as an active ingredient for preventing and / or treating a disease caused by Helicobacter pylori infection in a human or animal. will be.

A further object of the present invention is a Helicobacter pylori infection such as gastritis, ulcers (eg, peptic ulcers (eg, gastric ulcers, duodenal ulcers, anastomotic ulcers, etc.), etc.), MALT lymphoma, non-ulcer dyspepsia and gastric cancer in humans or animals To provide a treatment method for preventing and / or treating a disease caused by.

The cefem compound of the present invention can be represented by the following formula (I).

In Formula I,

R ¹ is aryl (lower) alkyl which may have 1 to 3 suitable substituents selected from the group consisting of lower alkyl, hydroxy and halogen which may form a ring with the carbon atom to which it is attached; Heterocyclic (lower) alkyl or cyano (lower) alkenylthio (lower) alkyl which may have from 1 to 3 suitable substituents selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and protected amino ego,

R ² is 1 selected from the group consisting of acyl (lower) alkyl, hydroxy (lower) alkyl, mono or di (lower) alkylamino (lower) alkyl, amino (lower) alkyl, acyl, acylamino and aryl with carboxy; Heterocyclic groups having from 3 suitable substituents, wherein the heterocyclic group may further have lower alkyl; Pyridyl (lower) alkyl; Pyrazolylethyl, which may have aryl (lower) alkyl; Thiadiazolyl (lower) alkyl; 5-aminothiazolyl; Thiadiazolyl with lower alkyl; Heterocyclic (lower) alkenyl which may have 1 to 3 suitable substituents or heterocyclicthio (lower) alkyl which may have 1 to 3 suitable substituents,

R ³ is carboxy or protected carboxy,

Provided that when R ¹ is aryl (lower) alkyl and R ² is thiadiazolyl having lower alkyl,

R ³ is acyloxy (lower) alkoxycarbonyl and 2) when R ¹ is aryl (lower) alkyl with halogen, R ² is not thiadiazolyl with lower alkyl and 3) R ¹ is aminothiazolyl In the case of (lower) alkyl, R ² is not thiadiazolyl with lower alkyl.

Cempem compound (I) or a salt thereof can be prepared by the method described in the following scheme.

In Schemes 1, 2, 3 and 4,

R ¹ , R ² and R ³ are each as described above,

R ⁴ is a leaving group,

R ⁵ is protected carboxy.

Starting compounds (II) and (IV) or salts thereof can be prepared by the methods described in the following schemes.

In Schemes A, B, C and D,

R^One, R², R³And R⁴Are as described above,

R ⁶ is protected amino.

Suitable examples of the various definitions of the cefe compound (I) of the invention, which fall within the scope of the invention, described herein, are described in detail below.

The term "lower" means a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.

“Aryl (lower) alkyl”, “heterocyclic (lower) alkyl”, “acyl (lower) alkyl”, “hydroxy (lower) alkyl”, “mono or di (lower) alkylamino (lower) alkyl”, Suitable "lower alkyl" and "lower alkyl" residues in "amino (lower) alkyl", "acylamino (lower) alkyl", "phenyl (lower) alkyl", etc. are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and straight or branched chains having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as t-butyl, pentyl, isopentyl and hexyl.

Suitable "halogens" may include chloro, bromo, fluoro and iodine.

Suitable "lower alkenyl" and "lower alkenyl" residues are 2 to 2, such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 1-pentenyl and 2-pentenyl It may comprise a straight or branched chain having 6 carbon atoms, preferably 2 to 4 carbon atoms.

Suitable "lower alkylidenes" may include straight or branched chains such as methylene, ethylidene, propylidene, vinylidene, butylidene, isopropylidene, pentidene, t-butylidene, hexylidene, and the like. But preferably (C ₁ -C ₄ ) alkylidene, most preferably propylidene.

Suitable "rings" in "lower alkyl capable of forming a ring with carbon atoms bonded to lower alkyl" thus may be cyclo (C ₃ -C ₆ ) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Which is preferably cyclo (C ₃ -C ₄ ) alkyl and most preferably cyclopropyl.

Suitable “aryl” moieties in “aryl (lower) alkyl” may include (C ₆ -C ₁₀ ) aryl such as phenyl, naphthyl, tolyl, xylyl, mesityl and cumenyl, more preferably Phenyl.

Preferred examples of “aryl (lower) alkyl” may include mono, di or tri aryl (lower) alkyl such as benzyl, pentyl, trityl, α-methylbenzyl and naphthylmethyl, more preferably phenyl ( Lower) alkyl, most preferably benzyl.

The "lower alkyl" and "aryl" residues in "aryl (lower) alkyl" may have one to three suitable substituents, such as lower alkyl, hydroxy, halogen, etc., which may form a ring with the carbon atom to which they are attached.

Suitable "heterocyclic" moieties in "heterocyclic (lower) alkyl", "heterocyclic group" and the like include, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyra containing 1 to 4 nitrogen atoms. Zolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1 Unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups such as 2,3-triazole, etc.), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.); Saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocylic groups containing 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl and the like Click group; Unsaturated condensation containing 1 to 4 nitrogen atoms, for example, indolyl, isoindoleyl, indolinyl, indolinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl and the like Heterocyclic group; For example, oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazole, 1,3,4-oxa containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms) Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups such as diazolyl, 1,2,5-oxadiazolyl and the like; Saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups such as, for example, morpholinyl, cydnonyl, etc. containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; Unsaturated condensed heterocyclic groups including, for example, benzoxazolyl, benzoxadiazolyl, containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; For example, thiazolyl, isothiazolyl, thiadiazolyl containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g. 1,2,3-thiadiazolyl, 1,2,4-thia Diazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc., unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocysis Click group; Saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups such as, for example, thiazolyldinyl, containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; Unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic groups, for example thienyl, dihydrodithiinyl, dihydrodithionyl, etc. containing 1 to 2 sulfur atoms: 1 Unsaturated condensed heterocyclic groups including, for example, benzothiazolyl, benzothiadiazolyl, 4,5,6,7-tetrahydrobenzothiazolyl, containing from 2 to 2 sulfur atoms and from 1 to 3 nitrogen atoms ; Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups such as, for example, furyl, including oxygen atoms; Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups such as, for example, dihydrooxathiinyl, including an oxygen atom and 1 to 2 sulfur atoms; Unsaturated condensed heterocyclic groups such as, for example, benzothienyl, benzodithiyl, etc. containing 1 to 2 sulfur atoms; Saturated or unsaturated monocyclics containing one or more oxygen, sulfur, nitrogen atoms, etc., including, for example, unsaturated condensed heterocyclic groups, such as benzoxathynyl, and the like, including oxygen atoms and one to two sulfur atoms. Heterocyclic groups or polycyclic heterocyclic groups.

Suitable "lower alkyl" residues in "heterocyclic (lower) alkyl" may be related to the "lower alkyl" described above, preferably (C ₁ -C ₄ ) alkyl, most preferably methyl.

Preferred examples of "heterocyclic (lower) alkyl" for R ¹ include lower alkyl having 1 to 2 membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 2 sulfur atoms and 1 Lower alkyl having an unsaturated 3 to 8 membered heteromonocyclic group containing from 3 to 3 nitrogen atoms, preferably thienyl (C ₁ -C ₄ ) alkyl, thiazolyl (C ₁ -C ₄ ) alkyl and thiadiazolyl (C ₁ -C ₄ ) alkyl, most preferably thienylmethyl, thiazolylmethyl and thiadiazolylmethyl.

Preferred examples of "heterocyclic group" for R ² include unsaturated 3 to 8 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. To unsaturated 3 to 8 membered heteromonocyclic groups and unsaturated condensed heterocyclic groups comprising 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, more preferably thiadiazolyl, Thiazolyl, triazolyl, tetrazolyl and tetrahydrobenzothiazolyl.

Suitable "acyl" and "acyl" residues in "acyl (lower) alkyl", "acylamino (lower) alkyl" or "acylamino" include carboxy, carbamoyl, thiocarbamoyl, aliphatic acyl groups, and aromatic acyls. Acyl groups including heterocyclic rings related to the aromatic ring or heterocyclic acyl involved.

Suitable examples of such acyl may be described as follows:

Carboxy;

Carbamoyl;

Thiocarbamoyl;

Lower or higher alkanoyls such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonano Day, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, isocanoyl, etc.) Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), lower or higher alkylsulfonyl (e.g. methylsulfonyl, Aliphatic acyl such as ethylsulfonyl), lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.);

Mono or di (lower) alkylaminocarbonyl (e.g. methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, propylaminocarbonyl, Butylaminocarbonyl, N-ethyl-N-propylaminocarbonyl, etc.);

Aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.), ar (lower) alkanoyl [e.g. phenyl (lower) alkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, Phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) alkanoyl (e.g. naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), and ar (lower) alkenoyl [e.g. phenyl ( Lower) alkenoyl (e.g. phenylpropenyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl (lower) alkenoyl (e.g. naphthylpropenoyl, naph Ylbutenoyl, etc.], ar (lower) alkoxycarbonyl [e.g., phenyl (lower) alkoxycarbonyl, such as benzyloxycarbonyl, etc.], aryloxycarbonyl (e.g., phenoxycarbonyl, naph Yloxycarbonyl, etc.), aryloxy (lower) alkanoyls (eg, phenoxyacetyl, phenoxypropionyl, etc.), arylcarbamoyl (eg, phenylcarbamoyl, etc.), arylthiocarbamoyl (eg, pe Thio-carbamoyl, etc.), aryl glyoxylic oil (e.g., phenyl glyoxylic oil, naphthyl glyoxylic oil and the like), arylsulfonyl (e.g., phenylsulfonyl, p- methoxybenzenesulfonyl sat some accounts, etc.), such as aromatic acyl;

Heterocyclic carbonyl, heterocyclic (lower) alkanoyl (e.g., heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, heterocyclicpentanoyl, heterocyclic hexanoyl, etc.), hetero Cyclic (lower) alkenoyl (e.g., heterocyclic propenoyl, heterocyclic butenoyl, heterocyclicpentenoyl, heterocyclic hexenoyl, etc.), heterocyclic glycoxyl oil, heterocyclic (lower) Heterocyclic acyls such as alkylcarbamoyl (eg, heterocyclic methyl carbamoyl, heterocyclic ethyl carbamoyl, heterocyclic propyl carbamoyl, heterocyclic hexyl carbamoyl, etc.), wherein the term "heterocyclic carba Suitable "heterocyclic" residues in the "mole", "heterocyclic (lower) alkanoyl", "heterocyclic (lower) alkenoyl" and "heterocyclicglyoxyl oil" Term "heterocyclic" residues.

Suitable “cyano (lower) alkenoylthio (lower) alkyl” include cyanovinylthiomethyl, cyanovinylthioethyl, cyanovinylthiopropyl, 3-cyano-1-propenylthiomethyl, 3-cyano -1-propenylthioethyl, cyanoallylthiomethyl and cyanoallylthioethyl, preferably cyano (C ₂ -C ₄ ) alkenylthio (C ₁ -C ₆ ) alkyl, Most preferably cyanovinylthiomethyl.

Suitable "lower alkyl" residues in "acyl (lower) alkyl" may be related to the "lower alkyl" described above, preferably (C ₁ -C ₄ ) alkyl, most preferably methyl and ethyl.

Suitable "acyl" residues in "acyl (lower) alkyl" may be related to "acyl" as described above, preferably carboxy, carbamoyl, mono or di (lower) alkylaminocarbonyl, lower alkoxycarbonyl, N Heterocyclic carbonyl, N-heterocyclic (lower) alkylcarbamoyl and thiocarbamoyl, most preferably carboxy, carbamoyl, dimethylaminocarbonyl, ethoxycarbonyl, methoxycarbonyl, morpholi Nocarbonyl, N-methylcarbamoyl, N-pyridylmethylcarbamoyl and thiocarbamoyl.

Preferred examples of “acyl (lower) alkyl” may include acyl (C ₁ -C ₄ ) alkyl, preferably carboxymethyl, carboxyethyl, carboxypropyl, carboxyisopropyl, carboxybutyl, carboxy-t-butyl Carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylisopropyl, carbamoylbutyl, carbamoyl-t-butyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, ethylaminocarbonylmethyl, diethylamino Carbonylethyl, propylaminocarbonylethyl, butylaminocarbonylpropyl, ethoxycarbonylmethyl, morpholinocarbonylmethyl, pyridylmethylcarbamoylmethyl, methoxycarbonylethyl and thiocarbamoylmethyl, most preferred Preferred are carboxymethyl, carbamoylmethyl, dimethylaminocarbonylmethyl, ethoxycarbonylmethyl, morpholinocarbonylmethyl, pyridylmethylcarbamoylmethyl, methoxycarbamoylethyl and thiocarbamoylmethyl.

Suitable "lower alkyl" residues in "hydroxy (lower) alkyl" may be related to the "lower alkyl" described above, preferably (C ₁ -C ₄ ) alkyl, most preferably methyl and ethyl.

Preferred examples of “hydroxy (lower) alkyl” may include hydroxy (C ₁ -C ₄ ) alkyl, more preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxy Hydroxybutyl and hydroxy-t-butyl, most preferably hydroxymethyl and hydroxyethyl.

Suitable “lower alkyl” residues in “mono or di (lower) alkylamino (lower) alkyl” may be related to the “lower alkyl” described above, preferably methyl.

Suitable "mono or di lower alkylamino" in "mono or di lower alkylamino (lower) alkyl" are methylamino, ethylamino, propylamino, isopropylamino, butylamino, t-butylamino, isobutylamino, pentylamino , Hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, diisopropylamino, dipentylamino, dihexylamino and N-methyl-N-ethylamino, preferably mono or Di (C ₁ -C ₄ ) alkylamino, most preferred is dimethylamino.

Preferred examples of “mono or di (lower) alkylamino (lower) alkyl” may include mono or di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl, more preferably methylamino Methyl, ethylaminoethyl, propylaminomethyl, isopropylaminopropyl, butylaminomethyl, t-butylaminoethyl, isobutylaminobutyl, dimethylaminomethyl, diethylaminoethyl, dipropylaminomethyl, dibutylaminopropyl, di Isopropylaminobutyl and N-methyl-N-ethylaminomethyl, most preferably dimethylaminomethyl.

Suitable "lower alkyl" in "amino (lower) alkyl" may be related to "lower alkyl" described above, preferably (C ₁ -C ₄ ) alkyl, most preferably methyl.

Preferred examples of “amino (lower) alkyl” may include amino (C ₁ -C ₄ ) alkyl, more preferably aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl and amino-t- Butyl, most preferably aminomethyl.

Suitable "lower alkyl" moieties in "protected amino (lower) alkyl" for R ² may be related to the "lower alkyl" described above, with preference given to (C ₁ -C ₄ ) alkyl, most preferred is methyl .

Suitable "protected amino" residues in "protected amino (lower) alkyl" may include acylamino.

Suitable "acyl" residues in the above "acylamino" may be related to the above "acyl", with preference being given to lower alkoxycarbonyl, more preferred to (C ₁ -C ₄ ) alkoxycarbonyl, most preferred t-butoxycarbonyl.

Preferred examples of “acylamino (lower) alkyl” may include lower alkoxycarbonylamino (lower) alkyl, more preferred is (C ₁ -C ₄ ) alkoxycarbonylamino (C ₁ -C ₄ ) alkyl And most preferred is t-butoxycarbonylaminomethyl.

Suitable "acyl" residues in "acylamino" may be related to the "acyl" described above, preferably carbamoyl and lower alkanoyl, most preferably carbamoyl, formyl and acetyl.

Preferred examples of “acylamino” may include ureido and alkanoylamino, preferably ureido and (C ₁ -C ₄ ) alkanoylamino, most preferably ureido, formylamino and acetylamino .

Suitable “aryl with carboxy” may include carboxyphenyl, carboxynaphthyl, carboxycyantril, and the like, most preferred is carboxyphenyl.

Suitable “pyridyl (lower) alkyl” may include pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, pyridylpentyl, pyridylhexyl, and the like, with preference given to pyridyl (C ₁ -C ₄₎ Alkyl, most preferred are pyridylmethyl and pyridylethyl.

Suitable "thiadiazolyl (lower) alkyl" may include thiadiazolylmethyl, thiadiazolylethyl, thiadiazolylpropyl, thiadiazolylbutyl, thiadiazolylpentyl, thiadiazolylhexyl, and the like. Thiadiazolyl (C ₁ -C ₄ ) alkyl, most preferably 1,2,3-thiadiazolylmethyl.

Suitable "heterocyclic" residues in "heterocyclic (lower) alkenyl" may be related to the "heterocyclic" residues described above, with preference being given to unsaturated 3 to 8 membered containing 1 to 4 nitrogen atoms. Heteromonocyclic groups, most preferred are pyridyl and pyrazolyl.

Suitable "lower alkenyl" residues in "heterocyclic (lower) alkenyl" may be related to the "lower alkenyl" residues described above, preferably (C ₂ -C ₄ ) alkenyl, most preferred Vinyl.

Preferred "heterocyclic (lower) alkenyl" moieties may include (C ₂ -C ₄ ) alkenyl having an unsaturated 3 to 8 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, Preferred are pyridylvinyl and pyrazolylvinyl.

Suitable "suitable substituents" in "heterocyclic (lower) alkenyl" which may have from 1 to 3 suitable substituents may include "acyl" as described above, with preference being given to aryl (lower) alkylcarbonyl, more Preferred is phenyl (C ₁ -C ₄ ) alkylcarbonyl and most preferred is benzylcarbonyl.

Suitable "heterocyclic" residues in "heterocyclic (lower) alkyl" which may have from 1 to 3 suitable substituents may be related to the "heterocyclic" residues described above, with 1 to 2 sulfur atoms being preferred. And unsaturated 3 to 8 membered heteromonocyclic groups containing 1 to 3 nitrogen atoms, most preferred is thiazolyl.

Preferred “heterocyclicthio (lower) alkyl” moieties are thio (C ₁ -C ₄ ) having unsaturated 3 to 8 membered heteromonocyclic groups comprising 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. Alkyl, preferably thiazolylthiomethyl.

Suitable "suitable substituents" in "heterocyclicthio (lower) alkyl" which may have from 1 to 3 suitable substituents may include the "acyl (lower) alkyl" described above, with carbamoyl (C _1-) being preferred. C ₄ ) alkyl, most preferred is carbamoylmethyl.

Suitable "protected carboxys" may include carboxy groups protected by conventional protecting groups such as esterified carboxy groups and the like, and specific examples are substituted or unsubstituted lower alkoxycarbonyls such as methoxycarbonyl, Ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 2- (dimethylamino) ethoxycarbonyl, 2-idoethoxycarbonyl , 2,2,2-trichloroethoxycarbonyl], substituted or unsubstituted aryloxycarbonyl (eg, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl) and Substituted or unsubstituted aryl (lower) alkoxycarbonyl, for example mono, di or triphenyl (lower) alkoxycarbonyl (eg benzyloxycarbonyl, petyloxycarbonyl, benzylhydryl) which may be substituted with nitro Oxycarbonyl and 4-nitrobenzyloxycarbonyl) and acyloxy (lower) eggs Carbonyl (e.g. t-butylcarbonyloxy-methyloxycarbonyl, 1-t-butylcarbonyloxy-1-methylmethyloxycarbonyl, 1-isopropylcarbonyloxy-1-methylmethyloxycarbonyl and 1-isobutylcarbonyloxy-1-methylmethyloxycarbonyl).

Suitable "leaving groups" include lower alkoxy (lower) alkoxy (e.g. methoxymethoxy), lower alkoxy (lower) alkoxy (lower) alkoxy (e.g. methoxyethoxymethoxy), substituted or unsubstituted aryl (lower) Lower alkoxy to be substituted, such as alkoxy (eg benzyloxy, nitrobenzyloxy); Lower alkanoyloxy (e.g. acetoxy, propionyloxy, pivaloyloxy), aroyloxy (e.g. benzoyloxy, fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g. methoxycarbonyloxy, Ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, t-butoxycarbonyloxy, pentyloxycarbonyloxy and hexyloxycarbonyloxy ), Substituted or unsubstituted aryl (lower) alkoxycarbonyloxy (e.g. benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy), arerensulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy), one Acyloxy such as alkanesulfonyloxy which may have any of the above suitable substituents such as methanesulfonyloxy, trifluoromethanesulfonyloxy and ethanesulfonyloxy; And tri (lower) alkylsilyloxy (eg trimethylsilyloxy).

Suitable “protected aminos” may include amino groups substituted by conventional protecting groups such as acylamino or ar (lower) alkyl which may have suitable substituents (eg benzyl, trityl, etc.) and the like.

Suitable "acyl" residues in the "acylamino" described above may be related to the "acyl" described above, with preference being given to lower alkanoyl, most preferred formyl and acetyl.

Preferred "protected amino" may include acylamino, with preference being lower alkanoylamino, most preferred formylamino and acetylamino.

Suitable salts of the desired compound (I) are pharmaceutically acceptable salts, such as conventional non-toxic salts, and organic acid addition salts such as formate, acetate, trifluoroacetate, malate, tartrate, methanesulfonate, Benzenesulfonate, p-toluenesulfonate), inorganic acid addition salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate), alkali metal salts (e.g. sodium salt, potassium salt), alkaline earth metal salts (e.g. calcium salt) , Magnesium salts).

Suitable examples of the salts of compounds (II), (III), (IV), (V), (VI), (VII) and (VIII) in Schemes 1 to 4 and Schemes A to D include It relates to what is described.

In particular, preferred examples of compound (I) in the present invention are as follows:

In compound (I),

R ¹ is aryl (lower) alkyl which may have 1 to 3 suitable substituents selected from the group consisting of lower alkyl, hydroxy and halogen which may form a ring with the carbon atom to which it is attached; An unsaturated 3-8 membered heterocyclic group containing 1 to 2 sulfur atoms which may have 1 to 3 suitable substituents selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and protected amino Lower alkyl or cyano (lower) alkenylthio (lower) alkyl having,

R ² has acyl (lower) alkyl, hydroxy (lower) alkyl, mono or di (lower) alkylamino (lower) alkyl, amino (lower) alkyl, acylamino (lower) alkyl, acyl, acylamino and carboxy Unsaturated heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms having 1 to 3 suitable substituents selected from the group consisting of aryl [the heterocyclic group may further have lower alkyl have]; Pyridyl (lower) alkyl; Pyrazolylethyl, which may have aryl (lower) alkyl; Thiadiazolyl (lower) alkyl; 5-aminothiazolyl; Thiazolyl with lower alkyl; Unsaturated 3 to 8 membered heteromonocyclic groups comprising 1 to 4 nitrogen atoms having an acyl (lower) alkyl; 1 to 2 sulfur atoms and 1 to 3 nitrogens which may have lower alkenyl or acyl (lower) alkyl having unsaturated 3 to 8 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms which may have acyl Lower alkylthio having an unsaturated 3 to 8 membered heteromonocyclic group containing an atom,

R ³ is carboxy or protected carboxy,

Provided that when R ¹ is aryl (lower) alkyl and R ² is thiadiazolyl containing lower alkyl, then R ³ is acyloxy (lower) alkoxycarbonyl, and 2) R ¹ is halogen having aryl (lower) ) if alkyl, R ² is not a case thiadiazolyl having lower alkyl, 3) R ¹ is an amino alkyl, thiazolyl (lower), R ² is not thiadiazolyl having lower alkyl.

In more preferred compound (I),

R ¹ is phenyl (lower) alkyl which may have 1 to 3 suitable substituents selected from the group consisting of lower alkyl, hydroxy and halogen which may form a 3-6 membered ring with the carbon atom to which it is attached; Thienyl (lower) alkyl, thiazolyl (lower) alkyl or thiadiazolyl (lower) which may each have 1 to 3 suitable substituents selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and acylamino Alkyl or cyano (lower) alkenylthio (lower) alkyl,

R ² is thiazolyl having 1 to 3 suitable substituents selected from the group consisting of acyl (lower) alkyl, hydroxy (lower) alkyl, acyl, acylamino and phenyl [the thiazolyl further has lower alkyl Can be; Thiadiazolyl having 1 to 3 suitable substituents selected from the group consisting of hydroxy (lower) alkyl, mono or di (lower) alkylamino (lower) alkyl and amino (lower) alkyl: pyridyl (lower) alkyl; Pyrazolylethyl, which may have trityl; Thiadiazolyl (lower) alkyl; 5-aminothiazolyl; 5-methyl-1,3,4-thiadiazolyl; Triazolyl with acyl (lower) alkyl; Tetrazolyl with acyl (lower) alkyl; Lower alkenyl having an unsaturated 3 to 8 membered heteromonocyclic group containing 1 to 4 nitrogen atoms which may have an acyl; Or lower alkenylthio having an unsaturated heteromonocyclic group comprising 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms which may have an acyl (lower) alkyl,

R ³ is carboxy or protected carboxy,

In more preferred compound (I),

R ¹ is phenyl (lower) alkyl, thienyl (lower) alkyl, thiazolyl (lower) alkyl or thiadiazolyl (lower) alkyl,

R ² is carboxy (lower) alkyl, carbamoyl (lower) acyl, mono or di lower alkylaminocarbonyl (lower) alkyl, hydroxy (lower) alkyl, carbamoyl, morpholinocarbonyl (lower) alkyl, pyri Thiazolyl having a suitable substituent selected from the group consisting of di (lower) alkylaminocarbonyl (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, thiocarbamoyl (lower) alkyl, ureido and phenyl containing carboxy Thiazolyl may further have lower alkyl; Thiadia with suitable substituents selected from the group consisting of hydroxy (lower) alkyl, di (lower) alkylamino (lower) alkyl, amino (lower) alkyl, lower alkoxycarbonylamino (lower) alkyl and carboxy (lower) alkyl Jolyl; Pyridyl (lower) alkyl; Pyrazolylethyl, which may have trityl; Thiadiazolyl (lower) alkyl; 5-aminothiazolyl; 5-methyl-1,3,4-thiadiazolyl; Triazolyl having a suitable substituent selected from the group consisting of carboxy (lower) alkyl and lower alkoxycarbonyl (lower) alkyl; Tetrazolyl with carboxy (lower) alkyl; Pyrazolyl (lower) alkenyl with pyridyl (lower) alkenyl or benzylcarbonyl,

R ³ is carboxy or protected carboxy,

In one more preferred compound (I),

R ¹ is phenyl (lower) alkyl,

R ² is carboxy (lower) alkyl, carbamoyl (lower) acyl, mono or di lower alkylaminocarbonyl (lower) alkyl, hydroxy (lower) alkyl, carbamoyl, morpholinocarbonyl (lower) alkyl, pyri Thiazolyl having suitable substituents selected from the group consisting of di (lower) alkylaminocarbonyl (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, thiocarbamoyl (lower) alkyl, ureido and phenyl with carboxy Thiazolyl may further have lower alkyl; Hydroxy (lower) alkyl, di (lower) alkylamino (lower) alkyl; Thiadiazolyl having suitable substituents selected from the group consisting of amino (lower) alkyl, lower alkoxycarbonylamino (lower) alkyl and carboxy (lower) alkyl; Pyridyl (lower) alkyl; Pyrazolylethyl, which may have trityl; Tyradiazolyl (lower) alkyl; 5-aminothiazolyl; 5-methyl-1,3,4-thiadiazolyl; Triazolyl having a suitable substituent selected from the group consisting of carboxy (lower) alkyl and lower alkoxycarbonyl (lower) alkyl, tetrazolyl having carboxy (lower) alkyl; Pyrazolyl (lower) alkenyl with pyridyl (lower) alkenyl or benzylcarbonyl,

R ³ is carboxy,

In another more preferred compound (I),

R ¹ is thienyl (lower) alkyl,

R ² is thiazolyl or thiazolyl having hydroxy (lower) alkyl with a suitable substituent selected from the group consisting of carboxy (lower) alkyl and carbamoyl (lower) acyl,

R ³ is carboxy,

In particularly preferred compound (I),

R ¹ is phenyl (lower) alkyl,

R ² is thiazolyl with carboxy (lower) alkyl or thiazolyl with carbamoyl (lower) alkyl,

R ³ is carboxy,

In another particularly preferred compound (I),

R ¹ is thienyl (lower) alkyl,

R ² is thiazolyl with carboxy (lower) alkyl or thiazolyl with carbamoyl (lower) alkyl,

R ³ is carboxy,

In the most preferred compound (I),

R ¹ is phenyl (lower) alkyl,

R ² is thiazolyl with carbamoyl (lower) alkyl,

R ³ is carboxy,

In particularly preferred compound (I),

R ¹ is thienyl (lower) alkyl,

R ² is thiazolyl with carbamoyl (lower) alkyl,

R ³ is carboxy.

In the present invention, a method for preparing the cefe compound (I) or a salt thereof is described in detail below.

Scheme 1

Compound (I) or a salt thereof can be prepared by reacting compound (II) or a salt thereof with compound (III) or a salt thereof.

Suitable salts of compound (III) include alkali metal salts such as sodium salts, potassium salts.

The reaction is generally carried out in the presence of a base. Suitable examples of bases include organic bases such as triethylamine, trimethylamine, N, N-diisopropylethylamine, dimethylamine, N-methylmorpholine and pyridine, alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), Inorganic bases such as alkali metal carbonates (eg sodium carbonate, potassium carbonate) and alkali metal bicarbonates (eg sodium bicarbonate, potassium hydrogen carbonate).

The reaction generally has adverse effects on solvents or reactions such as water, acetone, acetonitrile, dioxane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 1,2-dimethoxyethane, mixtures thereof It is carried out in certain other solvents which do not extend.

The reaction temperature is not critical and the reaction is generally carried out under cooling or heating.

Scheme 2

The desired compound (Ib) or a salt thereof can be prepared by removing the compound (Ia) or a salt thereof by removing a carboxy protecting group.

In this removal reaction, all conventional methods used to remove carboxy protecting groups are applicable, for example, hydrolysis, reduction, removal using Lewis acid, and the like. If the carboxy protecting group is an ester, it can be removed by hydrolysis or removal with Lewis acids. Hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases are, for example, alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. Magnesium carbonate, calcium carbonate), alkali metal bicarbonates (e.g. sodium bicarbonate, potassium hydrogen carbonate), alkali metal acetates (sodium acetate, potassium acetate), alkaline earth metal phosphates (e.g. magnesium phosphate, calcium phosphate) and alkali metal phosphate Inorganic bases such as anti-inflammatory salts (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate) and trialkylamines (e.g. trimethylamine, triethylamine), picoline, N-methylpyrrolidine, 1,5-diazabicyclo Organic bases such as [4.3.0] non-5-one, 1,4-diazabicyclo [2.2.2] octane and 1,5-diazabicyclo [5.4.0] undecane-5. Hydrolysis using bases is often carried out in water, hydrophilic organic solvents or mixed solvents thereof.

Suitable acids include organic acids such as formic acid, acetic acid and propionic acid and inorganic acids such as hydrochloric acid, bromic acid and sulfuric acid. The hydrolysis is generally carried out in water, organic solvents or mixed solvents thereof.

The reaction temperature is not critical and may be appropriately selected depending on the type of carboxy protecting group and the method of removal.

Removal reactions using Lewis acids are preferred for removing substituted or unsubstituted aryl (lower) alkyl esters, and are carried out by reacting Compound (Ia) or a salt thereof with Lewis acid. Examples of Lewis acids include boron trihalide (e.g. boron trichloride, boron trifluoride), titanium tetrachloride (e.g. titanium tetrachloride, titanium tetrabromide), tin halide (e.g. tin tetrachloride, tin tetrabromide), aluminum halides (e.g. Aluminum chloride, aluminum bromide) and trihaloacetic acid (such as trichloroacetic acid and trifluoroacetic acid). The removal reaction is preferably carried out in the presence of a cationic trapping agent (e.g. anisol, phenol), generally nitroalkanes (e.g. nitromethane, nitroethane), alkylene halides (e.g. methylene chloride, ethylene chloride) , Diethyl ether, carbon disulfide, or certain other solvents that do not adversely affect the reaction. These solvents may be used alone or in combination with each other.

The reduction elimination reaction preferably removes protecting groups such as halo (lower) alkyl (eg 2-iodoethyl, 2,2,2-trichloroethyl) esters and aryl (lower) alkyl (eg benzyl) esters. Can be done to

Reductions for application to elimination reactions can include binding of metals (eg zinc, amalgam zinc) or salts of chromium compounds (eg chromium chloride, chromium acetate), organic acids or inorganic acids (eg acetic acid, phosphoric acid, hydrochloric acid). Reduction in combination, and conventional catalytic reduction in the presence of conventional metal catalysts (eg palladium carbon, Raney nickel).

The reaction temperature is not critical and the reaction is generally carried out either under cold or at room temperature.

Scheme 3

Compound (I) or a salt thereof may be prepared by reacting compound (IV) or a reactive derivative thereof in an amino group or a salt thereof with compound (V) or a reactive derivative thereof in a carboxy group or a salt thereof.

Suitable reactive derivatives in the carboxy group of compound (V) include acid halides, acid anhydrides, activated amides and activated esters. Suitable examples of reactive derivatives include acid chlorides; Sanazide; Substituted phosphoric acid (e.g. dialkyl phosphate, phenyl phosphate. Diphenyl phosphoric acid, dibenzyl phosphate, halogenated phosphoric acid), dialkyl phosphate, sulfurous acid, thiosulfic acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid), aliphatic carboxylic acid ( Examples include acetic acid, phosphoric acid, butyric acid, mixed acid anhydrides with acids such as isobutyric acid, pivalic acid, pentanic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid) or aromatic carboxylic acids such as benzoic acid; Symmetric acid anhydrides; Amides activated with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; An activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyl-butylimino-methyl ^{_{[(CH 3) 2 N +}} = CH -] ester, vinyl ester, p-Pro way ester, p- nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester. Nyl esters, pyridyl esters, piperidyl esters, 8-quinolyl thioesters) or esters of N-hydroxy compounds (eg N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H)- Pyridone, N, -hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole). These reactive derivatives can be arbitrarily selected according to the kind of compound (V) used.

Suitable salts of compound (V) and its reactive derivatives include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts and organic base salts such as trimethylamine salts. And basic salts such as triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt).

Suitable reactive derivatives in the amino group of compound (IV) include their tautomeric enamine type isomers formed by reacting a carbonyl compound such as Schiff base type imino or an aldehyde or ketone with compound (IV); A silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide or bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide or bis (trimethylsilyl) urea is reacted with compound (IV) Formed silyl derivatives; Compound (IV) includes derivatives formed by reaction with phosphorus trichloride or phosgene.

The reaction is generally water, alcohols (eg methanol, ethanol), acetone, dioxane, acetonitrile, chloroform. Methylene chloride, ethylene chloride. It is carried out in solvents such as tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or certain other solvents that do not adversely affect the reaction. Such conventional solvents can be used in mixtures with water.

In this reaction. When compound (V) is used in free acid form or in salt form thereof, the reaction is preferably N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide; N, N'-diisopropylcarbodiimide; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis- (2-methylimidazole); Pentamethylene ketone-N-cyclohexylimine; Diphenylketone-N-cyclohexylimine; Ethoxyacetylene; 1-alkoxy-1-chloroethylene; Trialkyl phosphites; Ethyl polyphosphate; Isopropyl polyphosphate; Phosphorus oxychloride such as phosphoryl chloride; Phosphorus trichloride; Diphenyl phosphoryl azide; Thionyl chloride; Oxalin chloride; Lower alkyl haloformates (eg ethyl chloroformate, isopropyl chloroformate); Triphenylphosphine; 2-ethyl-7-hydroxybenz-isoxazolinium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolinium hydroxide intramolecular salt; Reaction of 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole or N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus acid chloride or oxalin chloride It is carried out in the presence of conventional condensing agents such as the so-called Vilsmeier reagent prepared.

The reaction is also carried out in the presence of an inorganic base or an organic base such as an alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine or N, N-di (lower) alkylbenzylamine.

The reaction temperature is not critical and is generally carried out under cooling or heating.

Scheme 4

The target compound (Ia) or a salt thereof can be prepared by protecting the carboxy of the compound (Ib) or a salt thereof.

The reaction can be carried out according to conventional methods as described in the Examples or similar methods.

The methods for preparing the starting compounds (II) and (IV) or salts thereof are described in detail below.

Scheme A

Compound (VII) or salts thereof can be prepared by removing the amino protecting group of compound (VI) or salts thereof in the presence of an acid.

Suitable acids include organic acids (eg formic acid, acetic acid, propionic acid) and inorganic acids (eg hydrochloric acid, bromic acid, sulfuric acid).

The reaction is generally carried out in solvents such as water, alcohols (eg methanol, ethanol), methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, mixtures thereof or certain other solvents that do not adversely affect the reaction.

The reaction temperature is not critical and is generally carried out under cooling or heating.

Scheme B

Compound (II) or a salt thereof may be prepared by reacting a reactive derivative or salt thereof at compound (VII) or an amino group with a reactive derivative or salt thereof at compound (V) or a carboxy group.

The reaction can be carried out substantially in the same way as in method 3 , so the reaction mode and reaction conditions (eg, reaction derivatives, condensing agents, solvents and reaction temperatures) of the reaction are as described in method 3 .

Scheme C

Compound (VIII) or a salt thereof can be prepared by reacting compound (VI) or a salt thereof with compound (III) or a salt thereof.

The reaction can be carried out substantially in the same manner as in Scheme 1 , so the reaction pattern and reaction conditions (eg, base, solvent, reaction temperature) of the reaction are as described in Scheme 1 .

Scheme D

Compound (IV) or a salt thereof can be prepared by removing the amino protecting group of Compound (VIII) or a salt thereof in the presence of an acid.

The reaction can be carried out substantially in the same manner as in Scheme A , so the reaction mode and reaction conditions (eg acid, solvent, reaction temperature) of the reaction are related to those described in Scheme A.

Starting compound (VI) can be manufactured by a well-known method as described in Unexamined-Japanese-Patent No. 52-83492.

Pulverization, recrystallization of the compound obtained by the above method. It can be separated and purified by conventional methods such as column chromatography or reprecipitation.

It should be noted that each of the compounds of interest (I) may comprise one or more stereoisomers such as optical isomers and geometric isomers due to asymmetric carbon atoms and double bonds, and all such isomers and mixtures thereof are included within the scope of the present invention. .

Cempem compound (I) and pharmaceutically acceptable salts thereof include solvent compounds such as inclusion compounds such as hydrates and the like.

Cempem compound (I) and pharmaceutically acceptable salts thereof include both their crystalline and amorphous forms.

Cempem compound (I) and pharmaceutically acceptable salts thereof are stable even in strong acids such as gastric juice.

Cempem compound (I) and pharmaceutically acceptable salts thereof include antimicrobial actives against H. pylori and prevent gastritis, ulcers (eg gastric ulcer, duodenal ulcer and anastomotic ulcer), MALT lymphoma and non-ulcer dyspepsia And / or treat and prevent gastric cancer. Cempem compound (I) and pharmaceutically acceptable salts thereof prevent and / or treat chronic gastritis, peptic ulcers (eg, gastric ulcer, duodenal ulcer and anastomotic ulcer), MALT lymphoma and non-ulcer dyspepsia, and prevent stomach cancer And may be administered in combination with acid secretion inhibitors such as H ₂ blockers (e.g. cimetidine, ranitidine, pamotidine, etc.) or proton pump inhibitors (e.g. omeprazole, lansoprazole, etc.).

Cempem compound (I) and pharmaceutically acceptable salts thereof are administered in particular with acid secretion inhibitors such as H ₂ blockers (e.g. cimetidine, ranitidine, pamotidine, etc.) or proton pump inhibitors (e.g. omeprazole, lansoprazole, etc.). To prevent diseases caused by Helicobacter pylori infections such as gastritis, ulcers (e.g. peptic ulcers (e.g. gastric ulcers, duodenal ulcers, anastomotic ulcers, etc.), MALT lymphoma, non-ulcer dyspepsia, and gastric cancer) It is effective to make or treat.

In particular, since the cefem compound (I) and pharmaceutically acceptable salts thereof have selective antimicrobial activity against H. pylori, they can act selectively against H. pylori without adversely affecting other useful enterobacteria. have. Thus, the cefem compound (I) and pharmaceutically acceptable salts thereof work well to eradicate H. pylori and are useful for treating ulcers and / or preventing recurrence of ulcers. Cempem compound (I) and pharmaceutically acceptable salts thereof can be treated with H ₂ blockers (e.g. cimetidine, ranitidine, pamotidine, etc.) or proton pump inhibitors (e.g. omeprazole) to treat ulcers and / or prevent recurrence of ulcers. In combination with an acid secretion inhibitor such as lansoprazole, and the like.

For therapeutic purposes, the cefem compound (I) and pharmaceutically acceptable salts thereof of the present invention are pharmaceutically acceptable such as organic solids or inorganic solids, or liquid excipients suitable for administration by themselves or orally or parenterally. It may be used in the form of a pharmaceutical preparation comprising one of the compounds as an active ingredient in a mixture with a carrier. The pharmaceutical preparation may be a capsule, tablet, sugar, granule, solution, suspension or emulsifier. Occasionally, auxiliary materials, stabilizers, wetting or emulsifiers, buffers and other commonly used additives (eg, lactose, sialic acid, magnesium stearate, terra alba, sucrose, corn starch, talc) in their preparation , Gelatin, agar, pectin, peanut oil, olive oil, cacao butter and ethylene glycol).

The dosage of compound (I) may vary depending on the age and condition of the patient, with an average single dose of compound (I) of about 0.1mg, 1mg, 10mg, 25mg, 50mg, 100mg, 0.1mg, 250mg, 500mg, 1000mg And 2000 mg will be effective in treating ulcers. Generally, an amount of 0.1 mg / body weight to about 2.000 mg / body weight may be administered per day.

When compound (I) is used in combination with an acid secretion inhibitor, the range of weight ratio of compound (I) to acid secretion inhibitor is as follows:

Compound (I) / Acid Secretion Inhibitor = 0.01 / 1-100/1

Preferred range

Compound (I) / Acid Secretion Inhibitor = 1/1-100/1

More preferred range

Compound (I) / Acid Secretion Inhibitor = 2.5 / 1-50/1

Another preferred range is

Compound (I) / acid secretion inhibitor = 0.1 / 1-10/1.

According to the invention it provides:

(1) Acid secretion as a combined method for use simultaneously, separately or continuously for preventing and / or treating a disease caused by a Hepobacter pylori infection with cefem compound (I) and pharmaceutically acceptable salts thereof Products comprising inhibitors.

(2) Cefem compound (I) and pharmaceutically acceptable salt and acid secretion inhibitors thereof for adjuvant treatment of diseases caused by Helicobacter pylori infection.

(3) secretion of the cefem compound (I) and pharmaceutically acceptable salts thereof and acid to prepare drugs for use simultaneously, individually or continuously to prevent and / or treat diseases caused by Helicobacter pylori infection Inhibitors.

(4) A product comprising cefem compound (I) and an acid secretion inhibitor for use simultaneously, separately or sequentially.

(5) A pharmaceutical composition comprising a cefem compound (I), an acid secretion inhibitor, and any pharmaceutically acceptable carrier or excipient.

(6) A pharmaceutical composition comprising only adjusting the composition for oral administration, comprising cefem compound (I) and a pharmaceutically acceptable salt and acid secretion inhibitor thereof as active ingredients.

(7) A product comprising cefem compound (I) or a pharmaceutically acceptable salt thereof (a) and an acid secretion inhibitor (b) in a weight ratio of 0.01 / 1 to 100/1.

(8) A method for treating or inhibiting a disease caused by Helicobacter pylori infection, comprising administering an effective amount of a cefem compound (I) to a patient in need of treating or inhibiting a disease caused by Helicobacter pylori infection.

(9) The method of the above (8), wherein the cefe compound (I) is combined with the acid secretion inhibitor in a weight ratio of the acid secretion inhibitor to the cefe compound (I) in the range of 0.01 / 1 to 100/1 and administered to the patient. .

10 cephem compound (I), including also a Helicobacter pylori administered to animals that need treatment of a disease caused by an infection with an effective amount, methods for the treatment of disorders of livestock animals infected with H. pylori.

(11) The method of (10), wherein the cefe compound (I) is administered to the patient in combination with the acid secretion inhibitor with the weight ratio of the acid secretion inhibitor to the cefe compound (I) in the range of 0.01 / 1 to 100/1. .

The pharmacological test data of representative compounds of compound (I) are shown below to illustrate the utility of the desired compound (I).

Test 1 ( antibacterial activity against Helicobacter pylori )

Test Methods

In vitro antimicrobial activity against Helicobacter pylori is determined by a 2-fold agar plate dilution method as described below.

Helicobacter pylori was incubated in Brussels agar plates containing 3% horse serum and 2% starch for 3 days at 37 ° C. under 10% CO ₂ and turbidity of McFar land 1 in Brucella broth. Suspend the road. The suspension was connected to Brucella agar suspended in 7% equine blood containing a gradient concentration of the test compound, and the minimum inhibitory concentration (MIC) was antimicrobially cultured at 37 ° C. under 10% CO ₂ for 3 days and then μg / Represented in ml.

Test compound

7β- (2-phenylacetamido) -3- (5-aminomethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid trifluoroacetic acid salt

Test result

MIC (µg / mL)

Test strain Test compound H. Pylori FP 1757 <0.02

Trial 2 (Therapeutic Effect in Mouse Model)

Test Methods

15 ml of 10 ⁸ cfu / ml H. pylori FP 1757 is infected for 4 weeks in the mouth of an old male ICR mice (Nippon SLC, Hamamatsu, Japan) fasted overnight. After infection for 4 days, the test compound is administered intramuscularly of the mice with a dose of 0.32 mg / kg / time twice daily for 4 days. Test compounds are suspended in 0.5% methylcellulose and administered to the mice. After the last dose, at 2 weeks, the gastric mucosa was scraped at the expense of the mice and homogenized in saline buffered with 1 ml of 0.1 M phosphoric acid. An aliquot of 0.1 ml is inoculated onto a Brucella agar plate containing 3% horse serum, 2% starch and antibiotics. All plates are incubated for 4-5 days at 37 ° C. under 10% CO ₂ . The effect of treatment is explained by counting the number of colonies grown on the plate.

Test compound

7β- [2- (2-trienyl) acetamido] -3- (4-carboxymethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid (compound of Example 72 )

Test result

Dose (mg / kg / time) Eradication rate (%) Test compound 0.32 ＞ 80%

Trial 3 [subacute toxicity]

Test Methods

Test compounds are suspended in 0.5% methylcellulose and administered intraorally in male rats at doses of 100-32 mg / kg / day for 2 weeks.

Test compound

7β- (2-phenylacetamido) -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid (compound of Example 14 )

Test result

Non-toxicological dose (mg / kg / day) Test compound 100

The following preparations and examples are given for the purpose of illustrating the invention in more detail.

Manufacture 1

To a solution of ethyl 2-mercapto-4-thiazole acetate (203 mg) in 1,4-dioxane (1.0 mL) is added 1 N sodium hydroxide solution (2.0 mL) at room temperature. After stirring for 2 hours at the same temperature, the solution is poured into a mixture of ethyl acetate and water and the pH is adjusted to 8.0 with 1N hydrochloric acid. The separated aqueous solution was adjusted to pH 3.0 with 1N hydrochloric acid and extracted using ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give 2-mercapto-4-thiazole acetic acid (120 mg).

NMR (DMSO-d ₆ , δ): 3.31 (1H, br s), 3.54 (2H, s), 6.72 (1H, s), 12.8 (1H, br, s)

Manufacture 2

To a solution of ethyl 2-mercapto-4-thiazole acetate (203 mg) in ammonia solution (25%, 1.0 ml) is added ammonium chloride (5.3 mg) at room temperature. After stirring for 8 hours at the same temperature, the solution is poured into a mixture of tetrahydrofuran and saturated sodium chloride solution and the pH is adjusted to 3.0 with 1N hydrochloric acid. The combined organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give 2-mercapto-4-thiazole acetamide (171 mg).

NMR (DMSO-d ₆ , δ): 3.36 (2H, s), 6.65 (1H, s), 7.08 (1H, br s), 7.47 (1H, br s), 13.07 (1H, br s)

APCI-MASS (m / z): 175 (M + H) ⁺

Manufacture 3

To a mixture of sodium hydroxide (24 mg) and N, N-dimethylformamide (4.0 mL) is added a dimethylamine solution (54 mg) at −10 ° C. in tetrahydrofuran (320 μl). After stirring for 1 hour at room temperature, ethyl 2-mercapto-4-thiazole acetate (203 mg) is added to the mixture at room temperature. After stirring for 3 hours at room temperature, the mixture is poured into a mixture of water and ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was charged by column chromatography on silica gel (eluent: ethyl acetate) to give N, N-dimethyl-2-mercapto-4-thiazole acetamide (72 mg).

NMR (DMSO-d ₆ , δ): 2.84 (3H, s), 3.00 (3H, s), 3.62 (2H, s), 6.63 (1H, s), 13.0 (1H, br s)

APCI-MASS (m / z): 203 (M + H) ⁺

Manufacture 4

To a solution of ethylene 2-mercapto-4-methyl-5-thiazole acetate (217 mg) in tetrahydrofuran (5.0 mL) is added lithium ammonium hydride (38 mg) under ice cooling. After stirring at 60 ° C. for 2 hours, the mixture is poured into a mixture of terahydrofuran and water and the pH is adjusted to 3.0 with 1N hydrochloric acid. The separated organic layer is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane / ethyl acetate = 2/3) to give 5- (2-hydroxyethyl) -2-mercapto-4-methylthiazole (89 mg). .

NMR (DMSO-d ₆ , δ): 2.05 (3H, s), 2.59 (2H, t, J = 6.1 Hz), 3.48 (2H, dt, J = 6.1 Hz and 5.2 Hz), 4.84 (1H, t, J = 5.2 Hz), 12.9 (1H, br s)

APCI-MASS (m / z): 196 (M + H) ⁺

Manufacture 5

4- (2-hydroxylethyl) -2-mercaptothiazole is obtained according to a method analogous to preparation 4 .

NMR (DMSO-d ₆ , δ): 2.59 (2H, t, J = 5.9 Hz), 3.61 (2H, dt, J = 6.3 Hz and 5.2 Hz), 4.77 (1H, t, J = 5.2 Hz), 6.59 (1H, s), 13.1 (1H, br s)

APCI-MASS (m / z): 162 (M + H) ⁺

According to a method similar to Preparation 1 , the following compounds ( Preparations 6 and 7 ) are obtained.

Manufacture 6

4- (2-carboxyethyl) -2-mercaptothiazole

NMR (DMSO-d ₆ , δ): 2.5-2.8 (4H, m), 6.58 (1H, s), 12.27 (1H, br s), 13.13 (1H, br s)

Manufacture 7

4- (carboxymethyl) -2-mercapto-4,5,6,7-tetrahydrobenzothiazole

NMR (DMSO-d ₆ , δ): 1.4-2.1 (4H, m), 2.3-2.6 (3H, m), 2.7-2.9 (1H, m), 2.8-3.1 (1H, m), 12.87 (1H, br s)

APCI-MASS (m / z): 230 (M + H) ⁺

Manufacture 8

According to a method similar to Preparation 2 , the following compounds are obtained.

4- (2-carboxymoylethyl) -2-mercaptothiazole

NMR (DMSO-d ₆ , δ): 2.3-2.6 (2H, m), 2.66 (2H, t, J = 7.2 Hz), 6.51 (1H, s), 6.87 (1H, br s), 7.36 (1H, 13.11 (1H, br)

Manufacture 9

Ammonium Dithiocarbamate in Water (10 mL) Ethyl bromopyruvate (1.95 g) and ethanol (5 mL) were added to ice solution (1.10 g) under ice-cooling. After stirring for 1 hour at room temperature, the mixture is poured into a mixture of water and ethyl acetate. The separated organic layer is washed with saturated sodium chloride solution (twice), dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give 4-ethoxycarbonyl-2-mercaptoazole (1.21 g).

NMR (DMSO-d ₆ , δ): 1.25 (3H, t, J = 7.1 Hz), 4.20 (2H, q, J = 7.1 Hz), 10.97 (1H, s)

APCI-MASS (m / z): 190 (M + H) ⁺

Manufacture 10

According to a method similar to Preparation 9 , the following compounds are obtained.

4-ethoxycarbonylmethyl-2-mercapto-4,5,6,7-tetrahydrobenzothiazole

NMR (DMSO-d ₆ , δ): 1.1-1.3 (3H, m), 1.4-2.0 (4H, m), 2.3-2.6 (3H, m), 2.7-2.9 (1H, m), 2.9-3.1 ( 1H, m), 4.0-4.2 (2H, m), 12.9 (1H, m)

APCI-MASS (m / z): 258 (M + H) ⁺

Manufacture 11

To a solution of 4-ethoxycarbonyl-2-mercaptothiazole (150 mg) in 0.8 ml of ammonia solution (25%, 0.8 ml) is added ammonium chloride (4.2 mg) at room temperature. After stirring for 8 hours at the same temperature, the solution is poured into a mixture of tetrahydrofuran and saturated sodium chloride solution and the pH is adjusted to 3.0 with 1N hydrochloric acid. The separated tetrahydrofuran solution is washed with saturated organic sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: chloroform / methanol) to give 4-carbamoyl-2-mercaptothiazole (70 mg).

NMR (DMSO-d ₆ , δ): 7.40 (1H, s), 7.45 (1H, br s), 7.62 (1H, br s)

APCI-MASS (m / z): 161 (M + H) ⁺

Manufacture 12

Bromine (26.2 g) is added to a solution of levulinic acid (19.0 g) in methanol (328 mL) at room temperature. After stirring for 4 hours at room temperature and refluxing for 1 hour, methanol is evaporated and the residue is poured into a mixture of water and ethyl acetate. The organic layer is washed with water, aqueous sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Diluted the residue (70-75 ° C./1 mm Hg) to afford methyl 5-bromorebulinate (15.0 g).

NMR (DMSO-d ₆ , δ): 2.66 (2H, t, J = 6.1 Hz), 2.96 (2H, t, J = 6.1 Hz), 3.69 (3H, s), 3.96 (2H, s).

Manufacture 13

To a mixture of methyl 5-bromourebrate (1.22 g), water (5.2 mL) and ethanol (2.6 mL) is added ammonium dithiocarbamate (642 mL) at room temperature. After stirring for 2 hours at room temperature, the obtained crystals were collected by filtration, first washed with a cold mixture of water and ethanol and then with diisopropyl ether (twice) to give 4- (2-methoxycarbo Yield ethyl-2-mercaptothiazole (0.61 g) is obtained.

NMR (DMSO-d ₆ , δ): 2.6-2.8 (4H, m), 3.60 (3H, s), 6.59 (1H, s), 13.15 (1H, br s)

APCI-MASS (m / z): 204 (M + H) ⁺

Manufacture 14

N-chlorosuccinimide (1.58 g) is added to a solution of 2-formamido-4-carboxymethylthiazole (2.0 g) in tetrahydrofuran (20 mL) and stirred overnight at room temperature. N-chlorosuccinimide (0.5 g) is added to the reaction mixture and stirred overnight at the same temperature. The reaction mixture is evaporated under reduced pressure and purified by column chromatography on silica gel (SiO ₂ = 200 mL, chloroform: methanol: acetic acid = 20: 1: 0.1) to give two fractions. Part 1 (top point of TLC) is purified by column chromatography on silica gel (SiO ₂ = 200 mL, methanol: chloroform = 2: 8) and the eluent is evaporated under reduced pressure. The residue is dissolved in a mixture of water and ethyl acetate, and then the pH is adjusted to 8.7 with saturated sodium hydrogen carbonate and washed with ethyl acetate (twice). The aqueous layer was adjusted with 1N hydrochloric acid, extracted with ethyl acetate (twice), dried over magnesium sulfate, evaporated under reduced pressure, and 5-chloro-2-formamido-4 as a white solid precipitated from ethyl acetate and N-hexane. -Carboxymethylthiazole (694 mg, 29.3%) is obtained as a white powder.

On the other hand, part 2 (bottom point of TLC) was evaporated under reduced pressure to precipitate from chloroform, methanol and isopropyl ether to be 5-chloro-2-formamidothiazol-4-yl- (R, S) -chloromethyl carboxylic acid (870 mg, 39.4%) is obtained.

[Upper spot]

NMR (DMSO-d ₆ , δ): 3.60 (2H, s), 8.51 (1H, s), 12.54 (1H, br s)

APCI-MASS (m / z): 221 (M + H) ⁺

[Bottom spot]

NMR (DMSO-d ₆ , δ): 5.28 (1H, s), 8.50 (1H, s)

APCI-MASS (m / z): 255 (M + H) ⁺

Manufacture 15

To a mixture of 5-amino-2-mercaptothiazole (6.61 g) in water (34 mL) and acetic acid (17 mL) is added a solution of sodium cyanate (6.50 g) in water (34 mL) at 35 ° C. After stirring for 2 hours at the same temperature, the solution is poured into a mixture of water, tetrahydrofuran and ethyl acetate and the pH is adjusted to 3.0 with 1N hydrochloric acid. The separated organic layer is washed with saturated sodium chloride solution (twice), dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-ureido-2-mercaptothiazole (557 mg).

NMR (DMSO-d ₆ , δ): 4.25 (2H, s), 7.45 (1H, s), 10.63 (1H, br s), 13.36 (1H, br s)

Manufacture 16

To the mixture with 2-mercaptothiazol-4-yl-acetamide (174 mg) and tetrahydrofuran (10 ml) is added Lawesson reagent (202 mg) at room temperature. After stirring overnight at room temperature, the solution is poured into a mixture of water and ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2-mercaptothiazol-4-yl-thioacetamide (188 mg).

NMR (DMSO-d ₆ , δ): 3.73 (2H, s), 6.68 (1H, s), 9.33 (1H, br s), 9.69 (1H, br s), 13.11 (1H, br s)

APCI-MASS (m / z): 191 (M + H) ⁺

Manufacture 17

Bromine (911 mg) is added to a solution of ethyl 2-cyclohexanone acetate (1.0 g) in dimethoxyethane (15 mL) under ice cooling. After stirring for 1 hour at room temperature, the solution is poured into a mixture with water and ethylene acetate. The separated organic layer is washed with aqueous sodium hydrogen sulfide, sodium hydrocarbon and saturated sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give ethyl 2-bromo-6-cyclohexanone acetate (258 mg).

NMR (DMSO-d ₆ , δ): 1.2-1.3 (3H, m), 1.3-1.9 (2H, m), 2.0-2.4 (5H, m), 2.6-2.9 (1H, m), 3.6-3.9 ( 1H, m), 4.1-4.3 (2H, m), 4.3-4.5 (1H, m)

APCI-MASS (m / z): 263 (M + H) ⁺

Manufacture 18

Benzhydryl 7β- (2-phenylacetamido) -3-trifluoromethanesulfonyloxy-3-cepem-4-carboxyl in a mixture of dichloromethane (27 mL) and anisol (27 mL) To the solution of rate (9.0 g) is added trifluoroacetic acid (18 ml) under ice cooling. The mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into diisopropyl ether (380 mL). The precipitate is collected by filtration and dried to give 7β- (2-phenylacetamido) -3-tripromethanesulfonyloxy-3-cepem-4-carboxylic acid (7.55 g).

NMR (DMSO-d ₆ , δ): 3.48 and 3.58 (2H, ABq, J = 14 Hz), 3.8 and 4.00 (2H, ABq, J = 18 Hz), 5.26 (1H, d, J = 5 Hz), 5.81 (1H , dd, J = 5 Hz and 8 Hz), 7.1-7.4 (5H, m), 9.24 (1H, d, J = 8 Hz)

Manufacture 19

To a mixture of ethyl 4- (bromoacetyl) benzoate (2 g), water (15 mL) and ethanol (14 mL) is added ammonium dithiocarbamate (813 mg) under stirring at room temperature. Stirring was continued for 1 hour at the same temperature, and the obtained crystals were collected by filtration. The crystals are added to a mixture of water (15 mL) and ethanol (15 mL) and the mixture is refluxed for 1 hour 30 minutes under stirring. Stirring is continued for 30 minutes at 10 ° C. to obtain crystals, collected by filtration and dried to give ethyl 4- (2-mercaptothiazol-4-yl) benzoate (1.15 g).

IR (KBr): 1699, 1608, 1587, 1456, 1290 cm ^-1

NMR (DMSO-d ₆ , δ): 1.34 (3H, t, J = 7.1 Hz), 4.33 (2H, q, J = 7.1 Hz), 7.53 (1H, s), 7.96 (4H, dd, J = 8.6 Hz and 8 Hz), 13.8 (1H, s)

APCI-MASS (m / z): 266 (M + H) ⁺

Manufacture 20

The following compounds are obtained following methods analogous to preparation 1 .

4- (2-mercaptothiazol-4-yl) benzoic acid

IR (KBr): 1685, 1608, 1556, 1477, 1403, 1249 cm ^-1

NMR (DMSO-d ₆ , δ): 7.51 (1H, s), 7.94 (4H, dd, J = 8.6 Hz and 22.1 Hz), 13.77 (1H, s)

APCI-MASS (m / z): 238 (M + H) ⁺

Example 1

To a solution of 2-mercapto-4-thiazole acetic acid (105 mg) in tetrahydrofuran (1.1 mL) and dimethoxyethane (1.1 mL) was added potassium t-butoxide (119 mg) at −10 ° C. and the solution was Stir at temperature for 20 minutes. On the other hand, benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cepem-4-carboxylate (267 mg) in tetrahydrofuran (1.3 mL) and dimethoxyethane (1.3 mL). Solution is added to the solution at -15 ° C. After stirring for 2 hours under ice cooling, the solution is poured into a mixture of water, ethyl acetate and tetrahydrofuran and the pH is adjusted to 3.0 with 1N hydrochloric acid. The separated organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / methanol = 8/1) to benzhydryl 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl ) Thio-3-cepem-4-carboxylate potassium salt (108 mg) is obtained.

NMR (DMSO-d ₆ , δ): 3.4-3.8 (6H, m), 5.16 (1H, d, J = 3.9 Hz), 5.52 (1H, dd, J = 3.9 Hz and 7.7 Hz), 6.87 (1H, s), 7.2-7.5 (15H, m), 7.61 (1H, s), 9.32 (1H, d, J = 7.7 Hz)

FBA-MASS (m / z): 696 (M + H) ⁺

The following compounds ( Examples 2-9 ) are obtained according to methods analogous to Example 1 .

Example 2

Benzhydryl 7β- (2-phenylacetamido) -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.53 (2H, dd, J = 13.9 Hz and 17.3 Hz), 3.57 (2H, s), 3.54 and 3.76 (2H, ABq, J = 17.7 Hz), 5.25 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.97 (1H, s), 7.01 (1H, br s), 7.2-7.5 (16H, m), 7.56 (1H , s), 9.26 (1H, d, J = 8.4 Hz)

APCI-MASS (m / z): 696 (M + H) ⁺

Example 3

Benzhydryl 7β- (2-phenylacetamido) -3- (5-carboxymethyl-4-methylthiazol-2-yl) thio-3-cefe-4-carboxylate potassium salt

NMR (DMSO-d ₆ , δ): 2.27 (3H, s), 3.4-3.9 (6H, m), 5.26 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.96 (1H, s), 7.1-7.5 (15H, m), 9.26 (1H, d, J = 8.4 Hz)

Example 4

Benzhydryl 7β- (2-phenylacetamido) -3- (4-N, N-dimethyl-carbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.83 (3H, s), 3.03 (3H, s), 3.53 (2H, d, J = 3.8 Hz), 3.54 and 3.75 (2H, ABq, J = 17.4 Hz), 3.84 (2H, s), 5.25 (1H, d, J = 5.0 Hz), 5.81 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.97 (1H, s), 7.1-7.5 (15H, m), 7.55 (1H, s), 9.26 (1H, d, J = 8.4 Hz)

Example 5

Benzhydryl 7β- (2-phenylacetamido) -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.52 (2H, d, J = 4.1 Hz), 3.61 and 3.89 (2H, ABq, J = 17.8 Hz), 4.84 (2H, s), 5.28 (1H, d, J = 5.0 Hz), 5.87 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.30 (1H, br s), 6.98 (1H, s), 7.2-7.5 (15H, m), 9.30 (1H, d, J = 8.4 Hz)

Example 6

Benzhydryl 7β- [2- (3-thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4- Carboxylate

NMR (CDCl ₃ , δ): 3.44 and 3.70 (2H, ABq, J = 17.9 Hz), 3.66 (2H, s), 4.98 (2H, s), 5.00 (1H, d, J = 5.0 Hz), 5.88 ( 1H, dd, J = 5.0 Hz and 9.1 Hz), 6.76 (1H, d, J = 9.1 Hz), 6.96 (1H, s), 6.9-7.4 (14H, m)

Example 7

Benzhydryl 7β- [2- (2-thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4- Carboxylate

NMR (CDCl ₃ , δ): 3.43 and 3.68 (2H, ABq, J = 18.1 Hz), 3.85 (2H, s), 5.00 (2H, s), 5.01 (1H, d, J = 5.1 Hz), 5.89 ( 1H, dd, J = 5.1 Hz and 9.1 Hz), 6.86 (1H, d, J = 9.1 Hz), 6.9-7.0 (3H, m), 7.1-7.4 (12H, m)

Example 8

Benzhydryl 7β- (2-phenylacetamido) -3- [4- (2-hydroxyethyl) -thiazol-2-yl] thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.86 (2H, t, J = 6.7 Hz), 3.4-3.9 (6H, m), 4.69 (1H, t, J = 5.3 Hz), 5.26 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.97 (1H, s), 7.2-7.5 (16H, m), 9.27 (1H, d, J = 8.4 Hz)

Example 9

Benzhydryl 7β- (2-phenylacetamido) -3- [5- (2-hydroxyethyl) -4-methylthiazol-2-yl] thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.29 (3H, s), 2.86 (2H, t, J = 6.1 Hz), 3.4-3.8 (6H, m), 4.92 (1H, t, J = 5.2 Hz), 5.25 (1H, d, J = 4.9 Hz), 5.80 (1H, d, J = 4.9 Hz and 8.3 Hz), 6.95 (1H, s), 7.2-7.6 (15H, m), 9.25 (1H, d, J = 8.4 Hz)

Example 10

To a solution of 2-mercapto-4-methyl-5-thiazole acetamido (489 mg) in tetrahydrofuran (4.9 mL) and dimethoxyethane (4.9 mL) potassium t-butoxide (224 mg) at −10 ° C. Is added and the solution is stirred at room temperature for 20 minutes. On the other hand, benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cepem-4-carboxylate (1.16 mg) in tetrahydrofuran (5.8 ml) and dimethoxyethane (5.8 ml) ) Is added to the solution at -15 ° C. After stirring for 2 hours under ice cooling, the solution is poured into a mixture of water and ethyl acetate. The obtained crystals were collected by filtration, washed with water and ethyl acetate to obtain benzhydryl 7β- (2-phenylacetamido) -3- (5-carbamoylmethyl-4-methylthiazol-2-yl) thio- Obtain 3-cepm-4-carboxylate (355 mg). The ethyl acetate layer of the filtrate is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate is added to the residue, the obtained crystals are collected by filtration and washed with ethyl acetate to give a second crystal (494 mg) of the desired compound.

NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 3.52 (2H, d, J = 3.2 Hz), 3.53 and 3.75 (2H, ABq, J = 17.7 Hz), 3.62 (2H, s), 5.26 (1H, d, J = 4.9 Hz), 5.81 (1H, dd, J = 4.9 Hz and 8.4 Hz), 6.96 (1H, s), 7.17 (1H, br s), 7.2-7.5 (15H, m) , 7.64 (1H, broad singlet), 9.28 (1H, doubled, J = 8.4 Hz)

Example 11

5-N, N-dimethylaminomethyl-2-mercapto-1,3,4-thiadiazole (364 mg) in a mixture of tetrahydrofuran (7 mL) and 1,2-dimethoxyethane (7 mL) To the solution of was added potassium t-butoxide (194 mg) with stirring at an ice bath temperature and the mixture was stirred at the same temperature for 30 minutes. Benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cepem-4-carboxylate (1.0 g) was added to the solution obtained at the same temperature, and the mixture was added at 4 at the same temperature. Stir for hours. The reaction mixture is poured into a mixture of 1N hydrochloric acid (1.64 ml), water (30 ml) and ethyl acetate (30 ml). The organic layer is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel (eluent: ethyl acetate / n-hexane = 3/1) to give 7β- (2-phenylacethio-3-cepem-4-carboxylate (310 mg).

NMR (DMSO-d ₆ , δ): 2.23 (6H, s), 3.53 (2H, m), 3.63 and 3.93 (2H, ABq, J = 18 Hz), 3.83 (2H, m), 5.28 (1H, d, J = 5Hz), 5.88 (1H, dd, J = 5Hz and 8Hz), 6.99 (1H, s), 7.2-7.4 (15H, m), 9.30 (1H, d, J = 8Hz)

Example 12

5-t-butoxycarbonylaminomethyl-2-mercapto-1,3,4-thiadiazole (580 mg) in a mixture of tetrahydrofuran (3 mL) and 1,2-dimethoxyethane (3 mL) To the solution of is added potassium t-butoxide (239 mg) with stirring at -9 ° C and the mixture is stirred for 30 minutes at a temperature of -9 to -5 ° C. Benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cepem-4 in a mixture of tetrahydrofuran (6 mL) and 1,2-dimethoxyethane (3 mL) -Carboxylate (1.23 g) is added to the solution obtained at -8 ° C and the mixture is stirred for 3 hours 30 minutes at a temperature of -5 to 0 ° C. The reaction mixture is poured into a mixture of cold water (50 mL) and ethyl acetate (50 mL). The organic layer is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was separated by column chromatography on silica gel to give benzhydryl 7β- (2-phenylacetamido) -3- (5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazole-2 -Yl) thio-3-cepem-4-carboxylate (0.82 g) is obtained.

NMR (DMSO-d ₆ , δ): 3.5 (2H, m), 3.57 and 3.89 (2H, ABq, J = 18 Hz), 4.47 (2H, d, J = 5 Hz), 5.27 (1H, d, J = 5 Hz ), 5.86 (1H, dd, J = 5 Hz and 8 Hz), 6.99 (1H, s), 7.2-7.4 (15H, m), 7.83 (1H, m), 9.28 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 730.2 (M ⁺ )

Example 13

Benzhydryl 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3-cepem-4-carboxylate potassium salt (1.10 g), anisol (1.10 mL) ) And difluoromethane (3.30 mL) are added trifluoroacetic acid (2.20 mL) at 15 ° C. After stirring for 1 hour at room temperature, the solution is poured into diisopropyl ether. The obtained precipitate is collected by filtration and added to a mixture of tetrahydrofuran and water to adjust the pH to 7.2 with aqueous sodium bicarbonate. The separated aqueous solution was adjusted to pH 3.0 with 1N hydrochloric acid and extracted with tetrahydrofuran. The tetrahydrofuran solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the obtained crystals were collected by filtration to obtain 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid ( 595 mg) is obtained.

IR (KBr): 1776, 1710, 1654, 1537 cm ^-1

NMR (DMSO-d ₆ , δ): 3.48 and 3.73 (2H, ABq, J = 17.5 Hz), 3.52 (2H, dd, J = 14 Hz and 17.6 Hz), 3.74 (2H, s), 5.19 (1H, d , J = 4.9 Hz), 5.73 (1H, dd, J = 5.0 Hz and 8.3 Hz), 7.1-7.4 (5H, m), 7.59 (1H, s), 9.19 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 492 (M + H) ⁺

The following compounds (Examples 14 to 21) were obtained according to a similar method as in Example 13.

Example 14

7β- (2-phenylacetamido) -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 3440, 3284, 1776, 1664, 1539, 1357cm ^-1

NMR (DMSO-d ₆ , δ): 3.52 (2H, dd, J = 13.9 Hz and 17.8 Hz), 3.55 (2H, s), 3.50 and 3.74 (2H, ABq, J = 17.6 Hz), 5.20 (1H, d, J = 4.9 Hz), 5.74 (1H, dd, J = 4.9 Hz and 8.4 Hz), 6.99 (1H, br s), 7.1-7.4 (5H, m), 7.43 (1H, br s), 7.53 ( 1H, s), 9.21 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 491 (M + H) ⁺

Example 15

7β- (2-phenylacetamido) -3- (5-carboxymethyl-4-methylthiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1776, 1718, 1657, 1539, 1367 cm ^-1

NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 3.52 (2H, dd, J = 13.8 Hz and 17.7 Hz), 3.48 and 3.72 (2H, ABq, J = 17.6 Hz), 3.83 (2H, s), 5.20 (1H, d, J = 4.9 Hz), 5.73 (1H, dd, J = 4.9 Hz and 8.4 Hz), 7.1-7.4 (5H, m), 9.22 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 506 (M + H) ⁺

Example 16

7β- (2-phenylacetamido) -3- (4-N, N-dimethylcarbamoylmethyl-thiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 3286, 1776, 1655, 1541, 1365cm ^-1

NMR (DMSO-d ₆ , δ): 2.84 (3H, s), 3.04 (3H, s), 3.52 (2H, s), 3.48 and 3.73 (2H, ABq, J = 17.6 Hz), 3.83 (2H, s ), 5.19 (1H, d, J = 4.9 Hz), 5.74 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1-7.4 (5H, m), 7.52 (1H, s), 9.21 (1H, d , J = 8.3 Hz)

FAB-MASS (m / z): 519 (M + H) ⁺

Example 17

7β- (2-phenylacetamido) -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1784, 1662, 1533 cm ^-1

NMR (DMSO-d ₆ , δ): 3.52 (2H, d, J = 4.2 Hz), 3.55 and 3.87 (2H, ABq, J = 17.7 Hz), 4.83 (2H, s), 5.23 (1H, d, J = 5.0 Hz), 5.79 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.29 (1H, br s), 7.2-7.4 (5H, m), 9.24 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 465.0 (M + H) ⁺

Example 18

7β-[(2- (3-thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1776, 1689, 1652, 1537 cm ^-1

NMR (DMSO-d ₆ , δ): 3.54 (2H, s), 3.56 and 3.88 (2H, ABq, J = 17.6 Hz), 4.83 (2H, s), 5.24 (1H, d, J = 5.0 Hz), 5.80 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.30 (1 H, br s), 7.0-7.5 (3 H, m), 9.21 (1 H, d, J = 8.4 Hz)

FAB-MASS (m / z): 470.9 (M + H) ⁺

Example 19

7β-[(2- (2-thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1776, 1689, 1652, 1539 cm ^-1

NMR (DMSO-d ₆ , δ): 3.56 and 3.88 (2H, ABq, J = 17.7 Hz), 3.76 (2H, s), 4.83 (2H, s), 5.25 (1H, d, J = 5.0 Hz), 5.80 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.30 (1H, br s), 6.9-7.0 (2H, m), 7.36 (1H, dd, J = 1.6 Hz and 4.9 Hz), 9.28 (1H , d, J = 8.4 Hz)

FAB-MASS (m / z): 470.9 (M + H) ⁺

Example 20

7β- (2-phenylacetamido) -3- [4- (2-hydroxyethyl) thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 1776, 1699, 1656, 1539 cm ^-1

NMR (DMSO-d ₆ , δ): 2.84 (2H, t, J = 6.7 Hz), 3.3-3.8 (6H, m), 4.67 (1H, br s), 5.21 (1H, d, J = 4.9 Hz) , 5.75 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1-7.4 (5H, m), 7.45 (1H, s), 9.22 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 477.9 (M + H) ⁺

Example 21

7β- (2-phenylacetamido) -3- [5- (2-hydroxyethyl) -4-methylthiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 1778, 1655, 1541 cm ^-1

NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 2.86 (2H, t, J = 6.1 Hz), 3.4-3.8 (6H, m), 4.91 (1H, br s), 5.19 (1H, d, J = 4.9 Hz), 5.72 (1H, dd, J = 4.9 Hz and 8.4 Hz), 7.1-7.4 (5H, m), 9.21 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 492.1 (M + H) ⁺

Example 22

Benzhydryl 7β- (2-phenylacetamido) -3- (5-carbamoylmethyl-4-methylthiazol-2-yl) thio-3-cepem-4-carboxylate (0.80 g), anisol (0.80 mL) and dichloromethane (2.40 mL) are added trifluoroacetic acid (1.60 mL) at 15 ° C. After stirring for 1 hour at room temperature the solution is poured into diisopropyl ether. The precipitate obtained is collected by filtration and added to a mixture of tetrahydrofuran and water to adjust the pH to 7.5 with aqueous sodium bicarbonate. The separated aqueous solution is washed with ethyl acetate and the pH is adjusted to 3.0 with 1N hydrochloric acid. The obtained crystals were collected by filtration to obtain 7β- (2-phenylacetamido) -3- (5-carbamoylmethyl-4-methylthiazol-2-yl) thio-3-cefe-4-carboxylic acid (445 mg). To obtain.

IR (KBr): 3423, 3298, 1778, 1660, 1540, 1365cm ^-1

NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 3.52 (2H, dd, J = 13.6 Hz and 17.5 Hz), 3.48 and 3.71 (2H, ABq, J = 17.5 Hz), 3.61 (2H, s), 5.20 (1H, d, J = 4.9 Hz), 5.73 (1H, dd, J = 4.9 Hz and 8.4 Hz), 7.14 (1H, br s), 7.1-7.4 (5H, m), 7.62 (1H , br s), 9.24 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 505 (M + H) ⁺

Example 23

Benzhydryl 7β- (2-phenylacetamido) -3- (5-N, N-dimethylaminomethyl-1,3,4- in a mixture of dichloromethane (0.9 mL) and anisol (0.47 mL) To a solution of thiadiazol-2-yl) thio-3-cepem-4-carboxylate (290 mg) is added trifluoroacetic acid (0.6 mL) under ice cooling. The mixture is stirred at rt for 1 h. The reaction mixture is poured into diisopropyl ether (30 mL), and the obtained precipitate is collected by filtration and dried under vacuum. The precipitate is dissolved in a mixture of aqueous sodium hydrogen carbonate solution (20 mL), tetrahydrofuran (10 mL) and ethyl acetate (20 mL). The mixture is adjusted to pH 2.0 with 1N hydrochloric acid. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β- (2-phenylacetamido) -3- (5-N, N-dimethylaminomethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem Obtain 4-carboxylic acid (150 mg).

IR (KBr): 3300-3200, 1770, 1720, 1660, 1530cm ^-1

NMR (DMSO-d ₆ , δ): 2.79 (6H, s), 3.4-3.6 (2H, m), 3.61 and 3.91 (2H, ABq, J = 18 Hz), 4.78 (2H, br s), 5.24 (1H , d, J = 5Hz), 5.79 (1H, dd, J = 5Hz and 8Hz), 7.2-7.3 (5H, m), 9.26 (1H, d, J = 8Hz)

FAB-MASS (m / z): 492 (M + H) ⁺

Example 24

Benzhydryl 7β- (2-phenylacetamido) -3- (5-t-butoxycarbonylaminomethyl-1,3,4 in a mixture of dichloromethane (2.1 mL) and anisol (0.7 mL) To a solution of -thiadiazol-2-yl) thio-3-cepem-4-carboxylate (683 mg) is added trifluoroacetic acid (1.4 mL) under ice cooling. The mixture is stirred at the same temperature for 30 minutes and at room temperature for 3 hours. The reaction mixture was collected by filtration and dried to 7β- (2-phenylacetamido) -3- (5-aminomethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4- Obtained carboxylic acid trifluoroacetic acid salt (525 mg).

IR (KBr): 1770, 1660, 1530, 1200cm ^-1

NMR (DMSO-d ₆ , δ): 3.4-3.6 (2H, m), 3.49 and 3.87 (2H, ABq, J = 17 Hz), 4.56 (2H, s), 5.21 (1H, d, J = 5 Hz), 5.76 (1H, dd, J = 5 Hz and 8 Hz), 7.27 (5H, m), 9.22 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 464.0 (M + H) ⁺

The following compounds (Examples 25 to 27) were obtained according to a similar method as in Example 13.

Example 25

7β- (2-phenylacetamido) -3- [4- (2-methoxycarbonylethyl) -thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 1782, 1728, 1693, 1662, 1539 cm ^-1

NMR (DMSO-d ₆ , δ): 2.70 (2H, t, J = 7.1 Hz), 2.97 (2H, t, J = 7.4 Hz), 3.52 (2H, d, J = 3.6 Hz), 3.59 (3H, s), 3.47 and 3.73 (2H, ABq, J = 17.5 Hz), 5.20 (1H, d, J = 4.9 Hz), 5.73 (1H, dd, J = 8.3 Hz), 7.2-7.4 (5H, m), 7.46 (1H, s), 9.18 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 520 (M + H) ⁺

Example 26

7β- (2-phenylacetamido) -3- [4- (2-carboxyethyl) thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 1778, 1699, 1660, 1535 cm ^-1

NMR (DMSO-d ₆ , δ): 2.61 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 7.3 Hz), 3.52 (2H, d, J = 4.3 Hz), 3.47 and 3.74 ( 2H, ABq, J = 17.5 Hz), 5.20 (1H, d, J = 4.9 Hz), 5.74 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1-7.4 (5H, m), 7.44 (1H, s), 9.21 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 506 (M + H) ⁺

Example 27

7β- (2-phenylacetamido) -3- (5-ureidothiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1772, 1664, 1527 cm ^-1

NMR (DMSO-d ₆ , δ): 3.52 (2H, d, J = 4.1HZ), 3.53 and 3.81 (2H, ABq, J = 17.5 Hz), 4.30 (2H, s), 5.23 (1H, d, J = 5.0 Hz), 5.75 (1H, dd, J = 5.0 Hz and 8.4 Hz), 7.1-7.4 (5H, m), 7.99 (1H, s), 9.21 (1H, d, J = 8.4 Hz), 10.73 ( 1H, s)

FAB-MASS (m / z): 491 (M + H) ⁺

The following compounds ( Examples 28 to 3 7 ) are obtained according to methods analogous to Example 22 .

Example 28

7β- (2-phenylacetamido) -3- [4- (N-methylcarbamoylmethyl) -thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 1776, 1658, 1652, 1538 cm ^-1

NMR (DMSO-d ₆ , δ): 2.59 (3H, d, J = 4.6 Hz), 3.52 (2H, d, J = 4.1 Hz), 3.56 (2H, s), 3.49 and 3.74 (2H, ABq, J = 17.5 Hz), 5.20 (1H, d, J = 4.9 Hz), 5.74 (1H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5H, m), 7.52 (1H, s), 7.89 (1H , m), 9.20 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 505 (M + H) ⁺

Example 29

7β- (2-phenylacetamido) -3- (4-morpholinocarbamoylmethyl-thiazol-2-yl) thio-3-cepem-4-carboxylate

IR (KBr): 1776, 1683, 1654, 1540cm ^-1

NMR (DMSO-d ₆ , δ): 3.4-3.6 (10H, m), 3.48 and 3.73 (2H, ABq, J = 17.5 Hz), 3.86 (2H, s), 5.19 (1H, d, J = 4.9 Hz ), 5.76 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1-7.4 (5H, m), 7.54 (1H, s), 9.19 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 561 (M + H) ⁺

Example 30

7β- (2-phenylacetamido) -3- {4- [N- (2-pyridylmethyl) -carbamoylmethyl] thiazol-2-yl} thio-3-cepem-4-carboxylic acid

IR (KBr): 1774, 1660, 1618, 1539 cm ^-1

NMR (DMSO-d ₆ , δ): 3.52 (2H, d, J = 3.8 Hz), 3.50 and 3.74 (2H, ABq, J = 17.5 Hz), 3.70 (2H, s), 4.39 (2H, d, J = 5.9 Hz), 5.17 (1H, d, J = 4.9 Hz), 5.74 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1-7.4 (7H, m), 7.58 (1H, s), 7.74 ( 1H, dt, J = 1.8 Hz and 7.7 Hz), 8.50 (1H, d, J = 4.0 Hz), 8.61 (1H, t, J = 6.0 Hz), 9.20 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 582 (M + H) ⁺

Example 31

7β- (2-phenylacetamido) -3- (4-carbamoylthiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1780, 1662, 1581, 1537cm ^-1

NMR (DMSO-d ₆ , δ): 3.53 (2H, d, J = 4.5 Hz), 3.60 and 3.93 (2H, ABq, J = 17.6 Hz), 5.22 (1H, d, J = 5.0 Hz), 5.78 ( 1H, dd, J = 5.0 Hz and 8.3 Hz), 7.2-7.4 (5H, m), 7.65 (1H, br s), 7.81 (1H, br s), 8.31 (1H, s), 9.23 (1H, d , J = 8.3 Hz)

FAB-MASS (m / z): 477 (M + H) ⁺

Example 32

7β- (2-phenylacetamido) -3- [4- (2-carbamoylethyl) thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 1774, 1683, 1660, 1531 cm ^-1

NMR (DMSO-d ₆ , δ): 2.3-2.5 (2H, m), 2.90 (2H, t, J = 7.7 Hz), 3.52 (2H, d, J = 4.2 Hz), 3.46 and 3.73 (2H, ABq , J = 17.5 Hz), 5.20 (1H, d, J = 4.9 Hz), 5.74 (1H, dd, J = 4.9 Hz and 8.3 Hz), 6.77 (1H, br s), 7.1-7.3 (6H, m) , 7.40 (1H, s), 9.19 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 505 (M + H) ⁺

Example 33

7β- [2- (3-thienyl) acetamido] -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1760, 1660, 1530cm ^-1

NMR (DMSO-d ₆ , δ): 3.55 (2H, s), 3.55 (2H, s), 3.51 and 3.75 (2H, ABq, J = 17.7 Hz), 5.20 (1H, d, J = 4.9 Hz), 5.75 (1H, dd, J = 4.9 and 8.3 Hz), 6.9-7.1 (2H, m), 7.25 (1H, m), 7.4-7.6 (3H, m), 9.18 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 497 (M + H) ⁺

Example 34

7β- [2- (3-thienyl) acetamido] -3- [4- (2-carboxylethyl) -thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 1770, 1690, 1650, 1530 cm ^-1

NMR (DMSO-d ₆ , δ): 2.61 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 7.3 Hz), 3.54 (2H, s), 3.47 and 3.75 (2H, ABq, J = 17.5 Hz), 5.21 (1H, d, J = 4.9 Hz), 5.74 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.44 (1H, s), 7.4-7.5 (1H, m), 9.16 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 512 (M + H) ⁺

Example 35

7β- [2- (2-thienyl) acetamido] -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1765, 1660, 1530cm ^-1

NMR (DMSO-d ₆ , δ): 3.55 (2H, s), 3.76 (2H, s), 3.48 and 3.75 (2H, ABq, J = 17.5 Hz), 5.21 (1H, d, J = 4.9 Hz), 5.75 (1H, dd, J = 4.9 and 8.3 Hz), 6.9-7.0 (2H, m), 6.99 (1H, br s), 7.36 (1H, dd, J = 1.5 Hz and 4.8 Hz), 7.44 (1H, br s), 7.52 (1H, s), 9.24 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 497 (M + H) ⁺

Example 36

7β- [2- (2-thienyl) acetamido] -3- [4- (2-carboxyethyl) -thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (new sol): 1765, 1680, 1650, 1520 cm ^-1

NMR (DMSO-d ₆ , δ): 2.61 (2H, t, J = 7.4 Hz), 2.93 (2H, t, J = 7.4 Hz), 3.5-3.9 (4H, m), 5.22 (1H, d, J = 4.9 Hz), 5.75 (1H, dd, J = 4.9 Hz and 8.4 Hz), 6.8-7.0 (2H, m), 7.3-7.5 (2H, m), 9.23 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 512 (M + H) ⁺

Example 37

7β- [2- (3-thienyl) acetamido] -3- (4-carboxymethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (KBr): 1774, 1704, 1652, 1533 cm ^-1

NMR (DMSO-d ₆ , δ): 3.54 (2H, s), 3.74 (2H, s), 3.47 and 3.75 (2H, ABq, J = 17.7 Hz), 5.20 (1H, d, J = 4.9 Hz), 5.75 (1H, dd, J = 4.9 and 8.4 Hz), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.4-7.5 (1H, m), 7.59 (1H, s), 9.19 ( 1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 498 (M + H) ⁺

Example 38

To a solution of 4-carbamoyl-2-mercaptothiazole (450 mL) in tetrahydrofuran (27 mL) and dimethoxyethane (27 mL) was added potassium t-butoxide (242 mg) at −10 ° C. and the solution Stir for 20 minutes at the same temperature. Meanwhile, benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cepem-4-carboxylate (1.25 g) in tetrahydrofuran (12.5 mL) and dimethoxyethane (12.5 mL) ) Is added to the solution at -15 ° C. After stirring for 2 hours under ice cooling, the solution is poured into a mixture of water and ethyl acetate. The separated organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give benzhydryl 7β- (2-phenylacetamido) -3- (4-carbamoylthiazol-2-yl) thio Obtain 3-cepem-4-carboxylate (0.86 g).

NMR (DMSO-d ₆ , δ): 3.54 (2H, d, J = 4.0 Hz), 3.65 and 3.94 (2H, ABq, J = 17.6 Hz), 5.27 (1H, d, J = 5.0 Hz), 5.86 ( 1H, dd, J = 5.Hz0 and 8.4Hz), 6.98 (1H, s), 7.1-7.5 (15H, m), 7.64 (1H, br s), 7.78 (1H, br s), 8.32 (1H, s), 9.26 (1H, doublet, J = 8.4 Hz)

FAB-MASS (m / z): 643 (M + H) ⁺

The following compounds ( Examples 28 to 3 7 ) are obtained according to methods analogous to Example 22 .

Example 39

Potassium Benzhydryl 7β- (2-phenylacetamido) -3- [4- (2-carboxyethyl) thiazol-2-yl] thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.5-2.6 (2H, m), 2.8-3.0 (2H, m), 3.56 (2H, s), 3.52 and 3.77 (2H, ABq, J = 17.3 Hz), 5.26 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.96 (1H, s), 7.1-7.5 (16H, m), 9.24 (1H, d, J = 8.4 Hz)

Example 40

Benzhydryl 7β- (2-phenylacetamido) -3- (5-ureidothiazol-2-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.52 (2H, d, J = 3.8 Hz), 3.57 and 3.85 (2H, ABq, J = 17.7 Hz), 4.32 (2H, s), 5.28 (1H, d, J = 5.0 Hz), 5.83 (1H, dd, J = 5.0 Hz and 8.4 Hz), 7.00 (1H, s), 7.1-7.5 (15H, m), 8.01 (1H, s), 9.25 (1H, d, J = 8.4 Hz), 10.75 (1 H, br s)

Example 41

Benzhydryl 7β- (2-phenylacetamido) -3- (4-thiocarbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.53 (2H, d, J = 3.4 Hz), 3.54 and 3.76 (2H, ABq, J = 17.9 Hz), 3.98 (2H, s), 5.24 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.97 (1H, s), 7.2-7.5 (15H, m), 7.61 (1H, s), 9.26 (1H, d, J = 8.4 Hz), 9.33 (1 H, br s), 9.63 (1 H, br s)

APCI-MASS (m / z): 673 (M + H) ⁺

Example 42

Potassium benzhydryl 7β- [2- (2-thienyl) acetamido] -3- [4- (2-carboxyethyl) thiazol-2-yl] thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.5-2.7 (2H, m), 2.8-3.0 (2H, m), 3.5-3.8 (4H, m), 5.27 (1H, d, J = 5.0 Hz), 5.83 (1H, dd, J = 5.0 Hz and 8.3 Hz), 6.9-7.0 (3H, m), 7.2-7.5 (12H, m), 9.28 (1H, d, J = 8.3 Hz)

Example 43

Potassium benzhydryl 7β- [2- (3-thienyl) acetamido] -3- (4-carboxymethylthiazol-2-yl] thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.54 (2H, s), 3.74 (2H, s), 3.52 and 3.75 (2H, ABq, J = 17.3 Hz), 5.27 (1H, d, J = 4.9 Hz), 5.83 (1H, dd, J = 4.9 Hz and 8.4 Hz), 6.9-7.1 (2H, m), 7.2-7.7 (13H, m), 9.23 (1H, d, J = 8.4 Hz)

APCI-MASS (m / z): 664 (M + H) ⁺

Example 44

Benzhydryl 7β- (2-phenylacetamido) -3- (4-thiocarbamoylmethylthiazol-2-yl) thio-3-cefe-4-carboxylate (1.46 g), anisol (1.46 mL ) And dichloromethane (4.38 mL) are added trifluoroacetic acid (2.92 mL) at 15 ° C. After stirring for 1 hour at room temperature, the solution is poured into diisopropyl ether. The precipitate obtained is collected by filtration and added to a mixture of tetrahydrofuran, ethyl acetate and water to adjust the pH to 7.5 with aqueous sodium hydrogen carbonate. The separated aqueous solution is washed with ethyl acetate, adjusted to pH 3.0 with 1N hydrochloric acid and extracted with tetrahydrofuran. The tetrahydrofuran solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative HPLC (eluent: pH 3 buffer / acetonitrile) to give 7β- (2-phenylacetamido) -3- (4-thiocarbamoylmethylthiazol-2-yl) thio-3- Cefem-4-carboxylic acid (62 mg) is obtained.

IR (KBr): 1774, 1660, 1537 cm ^-1

NMR (DMSO-d ₆ , δ): 3.52 (2H, d, J = 3.9 Hz), 3.49 and 3.74 (2H, ABq, J = 17.6 Hz), 3.97 (2H, s), 5.17 (1H, d, J = 4.9 Hz), 5.73 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1-7.4 (5H, m), 7.58 (1H, s), 9.21 (1H, d, J = 8.3 Hz), 9.32 ( 1H, 9.60 (1H, br)

FAB-MASS (m / z): 507 (M + H) ⁺

The following compounds ( Examples 45 to 46 ) are obtained according to methods analogous to Example 44 .

Example 45

7β- (2-phenylacetamido) -3- (4-carboxymethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl) -thio-3-cepem-4-carboxylic acid

[Polarized to R or S]

IR (KBr): 1784, 1693, 1666, 1533 cm ^-1

NMR (DMSO-d ₆ , δ): 1.3-2.1 (4H, m), 2.1-2.5 (1H, m), 2.6-2.9 (3H, m), 3.0-3.3 (1H, m), 3.52 (2H, d, J = 4.1 Hz), 3.40 and 3.72 (2H, ABq, J = 17.6 Hz), 5.19 (1H, d, J = 4.9 Hz), 5.73 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1 -7.4 (5H, m), 9.19 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 546 (M + H) ⁺

Example 46

7β- (2-phenylacetamido) -3- (4-carboxymethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl) thio-3-cepem-4-carboxylic acid

[Less polar with R or S]

IR (KBr): 1781, 1712, 1670, 1533cm ^-1

NMR (DMSO-d ₆ , δ): 1.4-2.1 (4H, m), 2.1-2.5 (1H, m), 2.6-2.9 (3H, m), 3.0-3.3 (1H, m), 3.52 (2H, d, J = 4.0 Hz), 3.40 and 3.75 (2H, ABq, J = 17.6 Hz), 5.19 (1H, d, J = 4.9 Hz), 5.73 (1H, dd, J = 4.9 Hz and 8.3 Hz), 7.1 -7.4 (5H, m), 9.18 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 546 (M + H) ⁺

Example 47

To a solution of 2- (2-mercaptothiazol-4-yl) acetamide (895 mg) in tetrahydrofuran (10.7 mL) and dimethoxyethane (10.7 mL) was added potassium t-butoxide (480 mg) at -10 ° C. Add and stir the solution for 20 minutes at the same temperature. On the other hand, benzhydryl 7β- [2- (3-thienyl) acetamido] -3-methanesulfonyloxy-3-cepem-4-carboxylate (2.5 g) in tetrahydrofuran (35 ml) was Add to the solution at 15 ° C. After stirring for 2 hours under ice cooling, the solution is poured into a mixture of water and ethyl acetate. The separated organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the obtained crystals were collected by filtration to obtain benzhydryl 7β- [2- (3-thienyl) acetamido] -3- (4-carbamoylmethylthiazol-2-yl) thio -3-cepem-4-carboxylate (1.64 g) is obtained.

IR (KBr): 1784, 1666, 1537 cm ^-1

NMR (DMSO-d ₆ , δ): 3.55 (2H, s), 3.57 (2H, s), 3.54 and 3.74 (2H, ABq, J = 17.7 Hz), 5.26 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.97 (1H, s), 7.0-7.1 (2H, m), 7.2-7.5 (13H, m), 7.56 (1H, s), 9.22 (1H , d, J = 8.4 Hz)

APCI-MASS (m / z): 663 (M + H) ⁺

The following compounds ( Examples 48 to 51) are obtained according to methods analogous to Example 47 .

Example 48

Benzhydryl 7β- (2-phenylacetamido) -3- (5-aminothiazol-2-yl) -thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.45 (2H, s), 3.53 (2H, d, J = 3.8 Hz), 5.20 (1H, d, J = 4.7 Hz), 5.71 (1H, dd, J = 4.7 Hz and 8.3 Hz), 6.31 (2H, br s), 6.87 (1H, s), 6.93 (1H, s), 7.2-7.6 (15H, m), 9.13 (1H, d, J = 8.3 Hz)

Example 49

Benzhydryl 7β- (2-phenylacetamido) -3- [4- (2-carbamoylethyl) thiazol-2-yl] -thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.4-2.5 (2H, m), 2.92 (2H, t, J = 7.9 Hz), 3.53 (2H, d, J = 3.3 Hz), 3.52 and 3.76 (2H, ABq , J = 17.7 Hz), 5.26 (1H, d, J = 5.0 Hz), 5.82 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.78 (1H, br s), 6.97 (1H, s), 7.2 -7.5 (17H, m), 9.24 (1H, d, J = 8.4 Hz)

Example 50

Benzhydryl 7β- (2-phenylacetamido) -3- [4- (2-methoxycarbonylethyl) thiazol-2-yl] thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.71 (2H, t, J = 7.3 Hz), 2.97 (2H, t, J = 7.3 Hz), 3.53 (2H, d, J = 3.6 Hz), 3.58 (3H, s), 3.54 and 3.76 (2H, ABq, J = 17.7 Hz), 5.26 (1H, d, J = 4.9 Hz), 5.82 (1H, dd, J = 4.9 Hz and 8.4 Hz), 6.96 (1H, s) , 7.1-7.5 (15H, m), 7.48 (1H, s), 9.24 (1H, d, J = 8.4 Hz)

Example 51

Benzhydryl 7β- [2-thienylacetamido] -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cepem-4-carboxylate

IR (KBr): 1780, 1666, 1537 cm ^-1

NMR (DMSO-d ₆ , δ): 3.57 (2H, s), 3.76 (2H, s), 3.52 and 3.78 (2H, ABq, J = 17.5 Hz), 5.27 (1H, d, J = 5.0 Hz), 5.83 (1H, dd, J = 5.0 Hz and 8.3 Hz), 6.9-7.1 (4H, m), 7.2-7.5 (12H, m), 7.55 (1H, s), 9.28 (1H, d, J = 8.3 Hz )

APCI-MASS (m / z): 663 (M + H) ⁺

Example 52

Phosphorous oxychloride (473 μl) was added dropwise to a mixture of N, N-dimethylformamide (388 μl) and ethyl acetate (1 mL) under ice cooling. After stirring for 10 minutes at the same temperature, the mixture is cooled until a precipitate is observed. Tetrahydrofuran (17 mL) is added to the suspension. The suspension is stirred at the same temperature for 30 minutes. To the suspension is added 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) acetic acid (1.0 g). The mixture is stirred at the same temperature for 30 minutes to obtain an activated acid solution. Meanwhile, a suspension of 7β-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid (1.16 g) in tetrahydrofuran (17 mL) To N-trimethylsilylacetamide (3.7 g) is added. The suspension is stirred at 20-40 ° C. for 40 minutes to give a clear solution. To this solution is added the activated acid solution prepared above at -20 ° C. The mixture is stirred at −20 to 5 ° C. for 40 minutes. The reaction mixture is added to a mixture of ethyl acetate (100 mL), sodium bicarbonate (1.59 g) and water (100 mL). Ethyl acetate (100 mL) is added to the separated aqueous solution. The mixture is adjusted to pH 2 with 1N hydrochloric acid. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β- [2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl- 1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid (1.17 g) is obtained.

NMR (DMSO-d ₆ , δ): 1.50 (9H, s), 2.72 (3H, s), 3.54 and 3.86 (2H, ABq, J = 17 Hz), 3.70 and 3.79 (2H, ABq, J = 15 Hz), 5.24 (1H, d, J = 5 Hz), 5.80 (1H, dd, J = 5 Hz and 8 Hz), 9.22 (1H, d, J = 8 Hz), 12.29 (1H, br s)

FAB-MASS (m / z): 572.0

The following compounds ( Examples 53 to 56) are obtained according to methods analogous to Example 52 .

Example 53

7β- [2- (5-chloro-2-formylaminothiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio- 3-cefe-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 2.72 (3H, s), 3.54 and 3.85 (2H, ABq, J = 17 Hz), 3.60 (2H, s), 5.23 (1H, d, J = 5 Hz), 5.79 ( 1H, dd, J = 5 Hz and 8 Hz), 8.49 (1H, s), 9.20 (1H, d, J = 8 Hz), 12.52 (1H, br s)

Example 54

7β- (1-phenyl-1-cyclopropanecarboxamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 1.0-1.2 (2H, m), 1.3-1.5 (2H, m), 2.72 (3H, s), 3.51 and 3.79 (2H, ABq, J = 17 Hz), 5.18 ( 1H, d, J = 5 Hz), 5.68 (1H, dd, J = 5 Hz and 8 Hz), 7.2-7.4 (5H, m), 7.74 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 475.1

Example 55

7β-[(Z) -2- (2-t-butoxycarbonylaminothiazol-4-yl) -2-pentenoylamino] -3- (5-methyl-1,3,4-thiadiazole -2-yl) thio-3-cepem-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 1.02 (3H, t, J = 6 Hz), 2.2-2.4 (2H, m), 2.72 (3H, s), 3.54 and 3.83 (2H, ABq, J = 17 Hz), 5.24 (1H, d, J = 5 Hz), 5.80 (1H, dd, J = 5 Hz and J = 8 Hz), 6.53 (1H, t, J = 7 Hz), 7.04 (1H, s), 8.87 (1H, d, J = 8 Hz), 11.57 (1H, s)

Example 56

Benzhydryl 7β- [2- (4-t-fluorophenyl) acetamido] -3-[(Z) -2- (3-pyridyl) vinylthio] -3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.50 and 3.56 (2H, ABq, J = 12 Hz), 3.82 and 4.09 (2H, ABq, J = 18 Hz), 5.20 (1H, d, J = 5 Hz), 5.77 (1H , dd, J = 5Hz and 8Hz), 6.75 (1H, d, J = 11Hz), 6.82 (1H, d, J = 11Hz), 6.93 (1H, s), 7.1-7.5 (15H, m), 7.7- 7.8 (1H, m), 8.4-8.5 (1H, m), 8.60 (1H, m), 9.21 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 638.1

Example 57

To a solution of 4-carboxymethyl-2-mercaptothiazole (719 mg) in a mixture of tetrahydrofuran (14 mL) and 1,2-dimethoxyethane (14 mL) with potassium t-butoxide (768 mg) with stirring under ice cooling ) Is added and the mixture is stirred at the same temperature for 1 hour. Benzhydryl 7β- [2- (2-thienyl) acetamido] -3-methanesulfonyloxy-3 in a mixture of tetrahydrofuran (10 mL) and 1,2-dimethoxyethane (10 mL) A solution of cefe-4-carboxylate (2.0 g) is added to the obtained potassium salt mixture at the same temperature and the mixture is stirred for 2 hours at a temperature of -5 to 0 ° C. The reaction mixture is poured into a mixture of cold water (100 mL) and ethyl acetate (150 mL). The mixture is adjusted to pH 7.0 with 1N sodium hydroxide solution. The separated organic layer is washed with 1N hydrochloric acid and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and ethyl acetate (2: 1) to form benzhydryl 7β- [2- (2-thienyl) acetamido] -3- (4-carboxymethylthiazol-2-yl ) Thio-3-cepem-4-carboxylate (687 mg) is obtained.

NMR (DMSO-d ₆ , δ): 3.57 and 3.79 (2H, ABq, J = 18 Hz), 3.7-3.8 (4H, m), 5.27 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 Hz and 8 Hz), 6.9-7.0 (1H, m), 6.93 (1H, s), 6.97 (1H, s), 7.2-7.4 (11H, m), 7.61 (1H, s), 9.27 (1H, d , J = 8 Hz)

According to a method similar to Example 57, the following compounds (Examples 58 to 62) are obtained.

Example 58

Benzhydryl 7β- (2-phenylacetamido)-(3-ethoxycarbonylmethyl-1,2,4-triazol-5-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 1.18 (3H, t, J = 7 Hz), 3.41 and 3.57 (2H, ABq, J = 17 Hz), 3.92 (2H, sb), 3.92 (2H, br s), 4.11 (2H, ABq, J = 7Hz), 5.23 (1H, d, J = 5Hz), 5.75 (1H, dd, J = 5Hz and 8Hz), 6.93 (1H, s), 7.2-7.6 (15H, m), 9.17 (1H, doublet, J = 8 Hz)

FAB-MASS (m / z): 670.1

Example 59

Benzhydryl 7β- (2-phenylacetamido) -3- (3-carboxymethyl-1,2,4-triazol-5-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.3-3.6 (4H, m), 3.78 (2H, s), 5.23 (1H, d, J = 5 Hz), 5.75 (1H, dd, J = 5 Hz and 8 Hz), 6.93 (1H, s), 7.2-7.5 (5H, m), 12.8 (1H, br s), 14.1 (1H, br s)

FAB-MASS (m / z): 642.0

Example 60

Benzhydryl 7β- (2-phenylacetamido) -3- (2-carboxymethyl-1,3,4-thiadiazol-5-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.3-3.7 (4H, m), 4.24 (2H, s), 5.28 (1H, d, J = 5 Hz), 5.87 (1H, dd, J = 5 Hz and 8 Hz), 6.95 (1H, s), 7.2-7.5 (15H, m), 9.29 (1H, d, J = 5 Hz)

FAB-MASS (m / z): 658.6

Example 61

Benzhydryl 7β- [2- (2-thienyl) acetamido] -3- [4- (2-carbamoylethyl) thiazol-2-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.44 (2H, t, J = 7 Hz), 2.91 (2H, t, J = 7 Hz), 3.52 and 3.78 (2H, ABq, J = 14 Hz), 3.76 (2H, s ), 5.28 (1H, d, J = 5 Hz), 5.86 (1H, dd, J = 5 Hz and 8 Hz), 6.81 (1H, br s), 6.9-7.0 (3H, m), 7.2-7.5 (13H, m ), 9.29 (1H, d, J = 5 Hz)

FAB-MASS (m / z): 676.9

Example 62

Benzhydryl 7β- [2- (3-thienyl) acetamido] -3- [4- (2-carbamoylethyl) thiazol-2-yl) thio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.44 (2H, t, J = 7 Hz), 2.92 (2H, t, J = 7 Hz), 3.55 (2H, s), 3.51 and 3.77 (2H, ABq, J = 14 Hz ), 5.22 (1H, d, J = 5 Hz), 5.84 (1H, dd, J = 5 Hz and 8 Hz), 6.81 (1H, br s), 6.97 (1H, s), 7.0-7.1 (1H, m), 7.2-7.5 (14H, m), 9.23 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 676.8

Example 63

To a solution of 3-benzoylthiomethylpyridine (950 mg) in dimethoxymethane (8 mL) is added 28% sodium methoxite methanol solution under ice cooling. The mixture is stirred at 5-8 ° C. for 30 minutes. The mixture was benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy- in dimethoxyethane (10 mL) and N, N-dimethylformamide (8 mL) for 5 minutes at -65 ° C. Add dropwise to a solution of 3-cepm-4-carboxylate. The mixture is stirred at -65 ° C for 60 minutes. Cooled buffer (pH 4, 100 mL) and ethyl acetate (100 mL) are added to the reaction mixture and the pH is adjusted to 6.7 with 1N sodium chloride solution. The separated organic layer was washed with water (100 mL x 3) and saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue is triturated with diethyl ether to give benzhydryl 7β- (2-phenylacetamido) -3- (pyridyl) methylthio-3-cepem-4-carboxylate (1.83 g).

NMR (DMSO-d ₆ , δ): 3.51 and 3.59 (2H, ABq, J = 14 Hz), 3.93 and 3.83 (2H, ABq, J = 18 Hz), 4.15 and 4.23 (2H, ABq, J = 14 Hz), 5.16 (1H, d, J = 5 Hz), 5.68 (1H, dd, J = 5 Hz and 8 Hz), 6.85 (1H, s), 7.2-7.4 (14H, m), 7.4-7.5 (2H, m), 7.6- 7.7 (1H, m), 8.4-8.5 (2H, m), 9.18 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 608.1

The following compounds ( Examples 64 to 69) are obtained according to methods analogous to Example 63 .

Example 64

Benzhydryl 7β- (2-phenylacetamido) -3- [2- (1-tritylpyrazol-4-yl) ethylthio] -3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.5-2.7 (2H, m), 2.9-3.1 (2H, m), 3.59 and 3.51 (2H, ABq, J = 14 Hz), 3.81 (2H, br s), 5.12 (1H, d, J = 5 Hz), 5.66 (1H, dd, J = 5 Hz and 8 Hz), 6.85 (1H, s), 7.0-7.6 (32H, m), 9.16 (1H, d, J = 8 Hz)

Example 65

Benzhydryl 7β- (2-phenylacetamido) -3- (1,2,3-thiadiazol-5-yl) methylthio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.50 and 3.58 (2H, ABq, J = 14 Hz), 3.79 and 3.89 (2H, ABq, J = 17 Hz), 4.66 (2H, s), 5.18 (1H, d, J = 5 Hz), 5.71 (1H, dd, J = 5 Hz and 8 Hz), 6.87 (1H, s), 7.2-7.5 (15H, m), 8.81 (1H, s), 9.18 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 615.0

Example 66

Benzhydryl 7β- (2-phenylacetamido) -3- [2- (3-pyridyl) -ethylthio] -3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 2.7-2.9 (2H, m), 3.1-3.2 (2H, m), 3.51 and 3.60 (2H, ABq, J = 14 Hz), 3.87 (2H, s), 5.16 ( 1H, d, J = 5Hz), 5.68 (1H, dd, J = 5Hz and 8Hz), 6.88 (1H, s), 7.2-7.7 (17H, m), 8.4-8.5 (2H, m), 9.16 (1H , d, J = 8 Hz)

FAB-MASS (m / z): 622.1

Example 67

Benzhydryl 7β- [2- (2-thienyl) acetamido) -3- (1,2,3-thiadiazol-5-yl) methylthio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.77 (2H, s), 3.81 and 3.91 (2H, ABq, J = 14 Hz), 4.66 (2H, s), 5.20 (1H, d, J = 5 Hz), 5.72 ( 1H, dd, J = 5Hz and 8Hz), 6.8-7.0 (3H, m), 7.2-7.5 (11H, m), 8.81 (1H, s), 9.20 (1H, d, J = 8Hz)

FAB-MASS (m / z): 620.9

Example 68

Benzhydryl 7β- (2-phenylacetamido) -3- (4-carbamoyl-methylthiazol-2-yl) thiomethylthio-3-cepem-4-carboxylate

NMR (DMSO-d ₆ , δ): 3.4-3.9 (8H, m), 5.26 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 Hz and 8 Hz), 6.97 (1H, s), 7.02 (1H, br s), 7.2-7.6 (16H, m), 7.56 (1H, s), 9.20 (1H, d, J = 8 Hz)

Example 69

Benzhydryl 7β-[(Z) -2- (2-cyanovinylthio) acetamido] -3- [2- (1-tritylpyrazol-4-yl) ethylthio] -3-cepem- 4-carboxylate

NMR (DMSO-d ₆ , δ): 2.5-2.7 (2H, m), 2.9-3.1 (2H, m), 3.75 (2H, s), 3.82 (2H, br s), 5.16 (1H, d, J = 5 Hz), 5.68 (1H, dd, J = 5 Hz and 8 Hz), 5.73 (1H, d, J = 10 Hz), 6.86 (1H, s), 6.9-7.6 (27H, m), 7.68 (1H, d, J = 10 Hz), 9.25 (1H, d, J = 8 Hz)

Example 70

Benzhydryl 7β- [2- (2-formylaminothiazol-4-yl) acetamido] -3- (5-methyl in a mixture of dichloromethane (3.6 mL) and anisol (1.2 mL) To a solution of -1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylate (1.2 g) is added trifluoroacetic acid (2.4 mL) under ice cooling. The mixture is stirred at the same temperature for 45 minutes. The reaction mixture is poured into diisopropyl ether (80 mL) and the resulting precipitate is collected by filtration and dried under vacuum. The precipitate is dissolved in a mixture of aqueous sodium hydrogen carbonate (40 mL), tetrahydrofuran (20 mL) and ethyl acetate (40 mL). To the separated aqueous solution is added ethyl acetate (40 mL) and tetrahydrofuran (20 mL). The mixture is adjusted to pH 1.8 with 1N hydrochloric acid. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β- [2- (2-formylaminothiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl ) Thio-3-cepem-4-carboxylic acid (490 mg) is obtained.

NMR (DMSO-d ₆ , δ): 2.72 (3H, s), 3.43 and 3.85 (2H, ABq, J = 17 Hz), 3.60 (2H, s), 5.23 (1H, d, J = 5 Hz), 5.80 ( 1H, dd, J = 5Hz and 8Hz), 6.95 (1H, s), 8.45 (1H, s), 9.11 (1H, d, J = 8Hz), 12.22 (1H, br s)

FAB-MASS (m / z): 499.0

The following compounds ( Examples 71 to 80 ) are obtained according to the method similar to Example 70 .

Example 71

7β- [2- (2-acetylaminothiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4 Carboxylate

NMR (DMSO-d ₆ , δ): 2.11 (3H, s), 2.72 (3H, s), 3.44 and 3.84 (2H, ABq, J = 17 Hz), 3.58 (2H, s), 5.22 (1H, d, J = 5Hz), 5.79 (1H, dd, J = 5Hz and 8Hz), 6.86 (1H, s), 9.09 (1H, d, J = 8Hz), 12.09 (1H, s)

FAB-MASS (m / z): 513

Example 72

7β- [2- (2-thienyl) acetamido] -3- (4-carboxymethylthiazol-2-yl) thio-3-cepem-4-carboxylic acid

IR (new sol): 3300, 1780, 1695, 1640, 1530, 1240cm ^-1

NMR (DMSO-d ₆ , δ): 3.48 and 3.75 (2H, ABq, J = 18 Hz), 3.7-3.8 (4H, m), 5.21 (1H, d, J = 5 Hz), 5.75 (1H, dd, J = 5 Hz and 8 Hz), 6.9-7.0 (1H, m), 6.92 (1H, s), 7.3-7.4 (1H, m), 7.59 (1H, s), 9.23 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 498.0

Example 73

7β- (2-phenylacetamido) -3- (5-ethoxycarbonylmethyl-1,2,4-triazol-3-yl) thio-3-cepem-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 1.19 (3H, t, J = 7 Hz), 3.3-3.6 (4H, m), 3.90 (2H, br s), 4.12 (2H, q, J = 7 Hz), 5.16 (1H, d, J = 5 Hz), 5.65 (1H, dd, J = 5 Hz and 8 Hz), 7.2-7.3 (5H, m), 9.12 (1H, d, J = 8 Hz), 13.7 (1H, br s) , 14.3 (1H, broad singlet)

FAB-MASS (m / z): 504.0

Example 74

7β- (2-tenylacetamido) -3-[(Z) -2- (3-pyridyl) vinylthio] -3-cepem-4-carboxylic acid

FAB-MASS (m / z): 454.0

Example 75

7β- [2- (4-fluorophenyl) acetamido] -3-[(Z) -2- (3-pyridyl) -vinylthio] -3-cepem-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 3.50 and 3.56 (2H, ABq, J = 14 Hz), 3.73 and 4.07 (2H, AB, J = 18 Hz), 5.15 (1H, d, J = 5 Hz), 5.70 (1H , dd, J = 5 Hz and 8 Hz), 6.78 (1H, d, J = 11 Hz), 6.8 (1H, d, J = 11 Hz), 7.0-7.2 (2H, m), 7.2-7.4 (2H, m), 7.4-7.5 (1H, m), 7.8-7.9 (1H, m), 8.4-8.5 (1H, m), 8.65 (1H, m), 9.17 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 472.1

Example 76

7β- (2-phenylacetamido) -3- (3-pyridyl) methylthio-3-cepem-4-carboxylic acid

IR (KBr): 3284, 3057, 3032, 1784, 1757, 1666, 1606, 1537, 1379, 1348, 1242cm ^-1

NMR (DMSO-d ₆ , δ): 3.49 and 3.58 (2H, ABq, J = 14 Hz), 3.79 (2H, s), 4.13 and 4.21 (2H, ABq, J = 12 Hz), 5.08 (1H, d, J = 5 Hz), 5.61 (1H, dd, J = 5 Hz and 8 Hz), 7.1-7.4 (5H, m), 7.3-7.5 (1H, m), 7.7-7.9 (1H, m), 8.4-8.6 (2H, m), 9.15 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 441.9

Example 77

7β- [2- (2-thienyl) acetamido] -3- [4- (2-carbomoylethyl) -thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 3405, 3280, 1774, 1689, 1664, 1535, 1433, 1412, 1365, 1282, 1242 cm ^-1

NMR (DMSO-d ₆ , δ): 2.43 (2H, t, J = 7 Hz), 2.90 (2H, t, J = 7 Hz), 3.47 and 3.75 (2H, ABq, J = 17 Hz), 3.76 (2H, s ), 5.23 (1H, d, J = 5 Hz), 5.75 (1H, dd, J = 5 Hz and 8 Hz), 6.80 (1H, br s), 6.9-7.0 (2H, m), 7.3-7.4 (3H, m ), 9.25 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 510.8

Example 78

7β- [2- (3-thienyl) acetamido] -3- [4- (2-carbamoylethyl) -thiazol-2-yl] thio-3-cepem-4-carboxylic acid

IR (KBr): 3406, 3294, 1772, 1657, 1535, 1365, 1242 cm ^-1

NMR (DMSO-d ₆ , δ): 2.43 (2H, t, J = 7 Hz), 2.90 (2H, t, J = 7 Hz), 3.47 and 3.75 (2H, ABq, J = 18 Hz), 3.54 (2H, s ), 5.22 (1H, d, J = 5 Hz), 5.75 (1H, dd, J = 5 Hz and 8 Hz), 6.80 (1H, br s), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m ), 7.34 (1H, broad s), 7.4-7.5 (2H, m), 9.18 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 510.8

Example 79

7β- (2-phenylacetamido) -3- (1,2,3-thiadiazol-5-yl) -methylthio-3-cepem-4-carboxylic acid

IR (KBr): 3440, 3890, 3340, 1770, 1680, 1535, 1360, 1240cm ^-1

NMR (DMSO-d ₆ , δ): 3.48 and 3.57 (2H, ABq, J = 14 Hz), 3.76 (2H, s), 4.67 (2H, s), 5.10 (1H, d, J = 5 Hz), 5.63 ( 1H, dd, J = 5Hz and 8Hz), 7.2-7.3 (5H, m), 8.85 (1H, s), 9.16 (1H, d, J = 8Hz)

FAB-MASS (m / z): 448.9

Example 80

7β- (2-phenylacetamido) -3-[(E) -2- (1-benzylcarbonyl-pyrazol-4-yl) vinylthio] -3-cepem-4-carboxylic acid

IR (new sol): 3250, 1760, 1690, 1650, 1520, 1230cm ^-1

NMR (DMSO-d ₆ , δ): 3.49 and 3.59 (2H, ABq, J = 14 Hz), 3.70 and 3.96 (2H, ABq, J = 17 Hz), 4.45 (2H, s), 5.15 (1H, d, J = 5 Hz), 5.65 (1H, dd, J = 5 and 8 Hz), 6.73 (1H, d, J = 15 Hz), 7.16 (1H, d, J = 15 Hz), 7.2-7.4 (10H, m), 8.20 ( 1H, s), 8.53 (1H, s), 9.14 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 561.3

Example 81

Benzhydryl 7β- (2-phenylacetamido) -3- (3-carboxymethyl-1,2,4-triazole-5 in a mixture of dichloromethane (1.2 mL) and anisol (0.4 mL) To a solution of -yl) thio-3-cepem-4-carboxylate (370 mg) is added trifluoroacetic acid (0.8 mL) under ice cooling. The mixture is stirred at room temperature for 50 minutes. The reaction mixture is poured into diisopropyl ether (30 mL) and the resulting precipitate is collected by filtration and dried under vacuum. The precipitate is dissolved in a mixture of aqueous sodium hydrogen carbonate (58 mg / 30 mL), tetrahydrofuran (10 mL) and ethyl acetate (30 mL). Tetrahydrofuran (10 mL) and ethyl acetate (30 mL) are added to the separated aqueous layer and the pH is adjusted to 2.0 with 1N hydrochloric acid. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue is triturated with isopropyl ether to afford the crude product (190 mg). The crude product (175 mg) was dissolved in a mixture of aqueous sodium bicarbonate and eluted with 20% acetonitrile-phosphate buffer (pH 3.0) with high performance liquid chromatography (HPLC) (R-ODS-C-15, YMC-pack Purified). The solution is concentrated in vacuo. Tetrahydrofuran (10 mL) and ethyl acetate (40 mL) were added to the resulting solution, and the pH was adjusted to 2.2 with 1 N hydrochloric acid. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give 7β- (2-phenylacetamido) -3- (5-carboxymethyl-1,2,4-thiazol-3-yl) thio-3-cepem-4-carboxylic acid ( 25.7 mg).

NMR (DMSO-d ₆ , δ): 3.3-3.6 (4H, m), 3.81 (2H, br s), 5.16 (1H, d, J = 5 Hz), 5.65 (1H, dd, J = 5 Hz and 8 Hz) , 7.1-7.3 (5H, m), 9.12 (1H, d, J = 8 Hz), 14.2 (1H, br s)

FAB-MASS (m / z): 476.0

The following compounds ( Examples 82-84 ) are obtained according to a method analogous to Example 81 .

Example 82

7β- (2-phenylacetamido) -3- (1-carboxymethyl-1,2,3,4-tetrazol-5-yl) thio-3-cepem-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 3.3-3.7 (4H, m), 5.19 (1H, d, J = 5 Hz), 5.40 and 5.51 (2H, AB, J = 18 Hz), 5.74 (1H, dd, J = 5 Hz and 8 Hz), 7.2-7.3 (5H, m), 9.13 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 476.9

Example 83

7β- (2-phenylacetamido) -3- (5-carboxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 3.48 and 3.57 (2H, ABq, J = 14 Hz), 3.54 and 3.87 (2H, ABq, J = 18 Hz), 4.24 (2H, s), 5.23 (1H, d, J = 5 Hz), 5.29 (1H, dd, J = 5 Hz and 8 Hz), 7.2-7.3 (1H, m), 9.24 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 492.8

Example 84

7β-[(2- (2-thienyl) acetamido] -3- (1,2,3-thiadiazol-5-yl) methylthio-3-cepem-4-carboxylic acid

IR (KBr): 3380, 1770, 1680, 1540, 1510, 1370, 1240cm ^-1

NMR (DMSO-d ₆ , δ): 3.76 (2H, br s), 3.76 (2H, br s), 4.62 (2H, s), 5.12 (1H, d, J = 5 Hz), 5.64 (1H, dd, J = 5 Hz and 8 Hz), 6.9-7.0 (2H, m), 7.3-7.4 (1H, m), 8.85 (1H, s), 9.17 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 454.57

Example 85

Benzhydryl 7β- (2-phenylacetamido) -3- [2- (1-tritylpyrazol-4-yl) ethyl in a mixture of dichloromethane (3 mL) and anisol (1 mL) To a solution of thio] -3-cepem-4-carboxylate (930 mg) is added trifluoroacetic acid (2 mL) under ice cooling. The mixture is stirred at rt for 1 h. The reaction mixture is poured into diisopropyl ether (100 mL). The precipitate is collected by filtration. 90% formic acid (4 mL) is added to the precipitate and stirred at room temperature for 15 minutes. The reaction mixture is poured into a mixture of ethyl acetate (100 mL) and ice water (50 mL). Buffer (pH 6.86, 100 mL) is added to the separated organic layer and the pH is adjusted to 7.0 with sodium bicarbonate. Ethyl acetate (60 mL) and tetrahydrofuran (30 mL) are added to the separated aqueous layer and the pH is adjusted to 2.5 with 1N hydrochloric acid. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β- (2-phenylacetamido) -3- [2- (pyrazol-4-yl) ethylthio] -3-cef-4-carboxylic acid (275 mg).

IR (KBr): 3400, 3270, 1780, 1660, 1540, 1360, 1290, 1240cm ^-1

NMR (DMSO-d ₆ , δ): 2.6-2.7 (2H, m), 3.00 (2H, t, J = 7 Hz), 3.49 and 3.58 (2H, ABq, J = 14 Hz), 3.72 and 3.81 (2H, ABq , J = 17 Hz), 5.10 (1H, d, J = 5 Hz), 5.60 (1H, dd, J = 5 Hz and 8 Hz), 7.2-7.3 (5H, m), 7.47 (2H, s), 9.14 (1H, d, J = 8 Hz), 13.0 (1H, br s)

The following compounds are obtained following the method analogous to Example 85 .

Example 86

7β-[(Z) -2- (2-cyanovinylthio) acetamido] -3- [2- (pyrazol-4-yl) ethylthio] -3-cepem-4-carboxylic acid

NMR (DMSO-d ₆ , δ): 2.6-2.7 (2H, m), 2.9-3.1 (2H, m), 3.70 and 3.82 (2H, ABq, J = 18 Hz), 3.74 (2H, s), 5.14 ( 1H, d, J = 5 Hz), 5.61 (1H, dd, J = 5 Hz and 8 Hz), 5.73 (1H, d, J = 10 Hz), 7.47 (2H, s), 7.67 (1H, d, J = 10 Hz) , 9.23 (1H, d, J = 8 Hz), 13.0 (1H, br s)

FAB-MASS (m / z): 451.9

Example 87

7β- [2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1 in dichloromethane (2.4 mL) To a solution of, 3,4-thiadiazol-2-yl) thio 3-cefe-4-carboxylic acid (800 mg) is added trifluoroacetic acid (10.4 mL). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into diisopropyl ether (100 mL). The precipitate is collected by filtration and dried. The precipitate is dissolved in a mixture of aqueous sodium hydrogen carbonate (212 mg / 30 mL) and tetrahydrofuran (10 mL). The solution is washed with ethyl acetate (30 mL). To the aqueous layer is added a mixture of tetrahydrofuran (15 mL) and ethyl acetate (45 mL) and the pH is adjusted to 2 with 1N hydrochloric acid. The organic layer is washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1,3,4- Tiadiazol-2-yl) thio-3-cepem-4-carboxylic acid (490 mg) is obtained.

NMR (DMSO-d ₆ , δ): 2.81 (3H, s), 3.59 and 3.67 (2H, ABq, J = 17 Hz), 3.61 and 3.93 (2H, ABq, J = 15 Hz), 5.32 (1H, d, J = 5 Hz), 5.88 (1H, dd, J = 5 Hz and 8 Hz), 7.97 (2H, br s), 9.22 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 471.9

The following compounds are obtained following the method analogous to Example 87 .

Example 88

7β-[(Z) -2- (2-aminothiazol-4-yl) -2-pentenoylamino] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio -3-cefe-4-carboxylic acid

IR (KBr): 3410, 3110, 2970, 1780, 1620, 1520, 1400, 1320, 1260, 1200cm ^-1

NMR (DMSO-d ₆ , δ): 1.01 (3H, t, J = 7 Hz), 2.34 (2H, dq, J = 7 Hz and 7 Hz), 3.53 and 3.83 (2H, ABq, J = 18 Hz), 5.26 (1H , d, J = 5 Hz), 5.86 (1H, dd, J = 5 Hz and 8 Hz), 6.49 (1H, s), 6.56 (1H, t, J = 7 Hz), 7.13 (2H, br s), 9.13 (1H , d, J = 8 Hz)

Example 89

Monotrimethylsilylacetamide (2.625 g) was added to a solution of 7β-amino-3- (pyrazol-4-yl) methylthio-3-cepem-4-carboxylic acid (625 mg) in dichloromethane (6 mL). The solution is stirred under reflux for 1 hour to obtain a solution comprising silylated cefem (solution 1). To a solution of R-(-)-mandelic acid (304 g), N, N-dimethylaminopyridine (catalyst amount) and pyridine (0.33 mL) in dichloromethane (4 mL) was added trimethylsilyl chloride (0.52 mL) to room temperature. Stir for 1 h. N, N-dimethylformamide (2 drops) and oxalic acid chloride (0.18 mL) were added continuously to the solution at 0 ° C., stirred at the same temperature for 1 hour and stirred at room temperature for 30 minutes. Solution 1 is added to the solution obtained at 0 ° C. and stirred at 0 ° C. for 2 hours. The resulting solution is added to a solution of citric acid (423 mL) in methanol (50 mL) and the mixture is stirred at 0 ° C. for 30 minutes.

The reaction mixture is quenched with water (100 mL) and the pH is adjusted to 7.2-7.5 with sodium bicarbonate and washed with ethyl acetate (100 mL). The aqueous layer is adjusted to pH 3.0 with 1N hydrochloric acid and washed (3 times) with a mixture of ethyl acetate and tetrahydrofuran (10: 1). The combined extracts are washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ethyl acetate and diethyl ether to prepare preparative HPL [column, YMC P-ODS-15C and guardgen, mobile phase; Phosphoric acid buffer (pH 6.0): acetonitrile = 85:15]).

The obtained eluate was adjusted to pH 3.0 with 1N hydrochloric acid and extracted (3 times) with a mixture of ethyl acetate and tetrahydrofuran (10: 1). The combined extracts are washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was precipitated from chloroform, methanol and isopropyl ether to yield 7β-[(R) -2-hydroxy-2-phenylacetamido] -3- (pyrazol-4-yl) methylthio-3-cepem as a powder. Obtain 4-carboxylic acid (60.5 mg).

IR (KBr): 1770, 1680cm ^-1

NMR (DMSO-d ₆ , δ): 3.76 (3H, s), 4.01 (2H, s), 5.06-5.11 (2H, m), 5.59 (1H, dd, J = 4.7 Hz and 8.8 Hz), 6.15 ( 1H, d, J = 5.5 Hz), 7.20-7.47 (5H, m), 7.55 (2H, s), 8.77 (1H, d, J = 8.9 Hz)

FAB-MASS (m / z): 447 (M + H) ⁺

The following compounds are obtained following the method analogous to Example 89 .

Example 90

7β-[(S) -2-hydroxy-2-phenylacetamido] -3- (pyrazol-4-yl) -methylthio-3-cepem-4-carboxylic acid

IR (KBr): 1770, 1678cm ^-1

NMR (DMSO-d ₆ , δ): 3.80 (2H, s), 4.02 (2H, s), 5.04-5.10 (2H, m), 5.54 (1H, dd, J = 4.6 Hz and 8.7 Hz), 7.20- 7.46 (5H, m), 7.56 (2H, s), 8.67 (1H, d, J = 8.7 Hz)

FAB-MASS (m / z): 447 (M + H) ⁺

Example 91

Benzhydryl 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3 in dichloromethane (20 mL) and N, N-dimethylformamide (20 mL) Add 1-hydroxybenzotriazole (247 mg), WSC.HCl (349 mL) and 2M-methylamine tetrahydrofuran solution (0.91 mL) to a solution of cefem-4-carboxylate (1.0 g) at room temperature. . After stirring for 2 hours at room temperature, the solution is poured into a mixture of water and ethyl acetate. The separated organic layer is washed with saturated sodium chloride solution (3 times), dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the obtained crystals were collected by filtration to obtain benzhydryl 7β- (2-phenylacetamido) -3- [4- (N-methylcarbamoylmethyl) thiazol-2-yl] thio -3-cefem-4-carboxylate (186 mg) is obtained.

NMR (DMSO-d ₆ , δ): 2.59 (3H, d, J = 4.6 Hz), 3.53 (2H, d, J = 3.7 Hz), 3.58 (2H, s), 3.48 and 3.77 (2H, ABq, J = 17.7 Hz), 5.25 (1H, d, J = 5.0 Hz), 5.81 (1H, dd, J = 5.0 Hz and 8.5 Hz), 6.97 (1H, s), 7.2-7.5 (15H, m), 7.55 ( 1H, s), 7.92 (1H, m), 9.24 (1H, d, J = 8.5 Hz)

Example 92

Benzhydryl 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3-cepem-4-carboxylate in N, N-dimethylformamide (10 mg) To 500 g) is added 1-hydroxybenzotriazole (123 mg), WSC.HCl (349 mL) and morpholine (79 mg) at room temperature. After stirring for 2 hours and 30 minutes at room temperature, the solution is poured into a mixture of water and ethyl acetate and the pH is adjusted to 7.0 with aqueous sodium hydrogen carbonate. The separated organic layer is washed with saturated sodium chloride solution (3 times), dried over magnesium sulfate and evaporated under reduced pressure. The residue was separated by column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give benzhydryl 7β- (2-phenylacetamido) -3- (4-morpholinocarbonylmethylthiazole-2 -Yl) thio-3-cepem-4-carboxylate (147 mg) is obtained.

NMR (DMSO-d ₆ , δ): 3.4-3.6 (10H, m), 3.48 and 3.76 (2H, ABq, J = 17.3 Hz), 3.87 (2H, s), 5.25 (1H, d, J = 5.0 Hz ), 5.81 (1H, dd, J = 5.0 Hz and 8.5 Hz), 6.97 (1H, s), 7.2-7.5 (15H, m), 7.57 (1H, s), 9.23 (1H, d, J = 8.5 Hz )

Example 93

Benzhydryl 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3- in dichloromethane (10 mL) and N, N-dimethylformamide (10 mg) To a solution of cefem-4-carboxylate (500 mg) is added 1-hydroxybenzotriazole (123 mg), WSC.HCl (175 mL) and 2-aminomethylpyridine (99 mg) at room temperature. After stirring for 3 hours at room temperature, the solution is poured into a mixture of water and ethyl acetate and the pH is adjusted to 7.0 with aqueous sodium bicarbonate. The separated organic layer is washed with saturated sodium chloride solution (3 times), dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the obtained crystals were collected by filtration to collect benzhydryl 7β- (2-phenylacetamido) -3- {4- [N- (2-pyridylmethyl) carbamoylmethyl] thiazole 2-yl] thio-3-cepem-4-carboxylate (178 mg) is obtained.

NMR (DMSO-d ₆ , δ): 3.53 (2H, d, J = 3.8 Hz), 3.54 and 3.78 (2H, ABq, J = 17.5 Hz), 3.72 (2H, s), 4.39 (2H, d, J = 5.9 Hz), 5.23 (1H, d, J = 5.0 Hz), 5.81 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.94 (1H, s), 7.2-7.5 (17H, m), 7.61 ( 1H, s), 7.71 (1H, dt, J = 1.8 Hz and 7.7 Hz), 8.48 (1H, d, J = 4.0 Hz), 8.67 (1H, t, J = 6.0 Hz), 9.26 (1H, d, J = 8.4 Hz)

Example 94

Benzhydryl 7β- (2-phenylacetamido) -3- (5-aminothiazol-2-yl) thio-3-cepem-4-carboxylate (1.47 g) with dichloromethane (4.41 mL) To the mixture of trifluoroacetic acid (2.94 ml) and anisol (1.47 ml) under ice-cooling are added under ice-cooling. After stirring for 1 hour at room temperature, the solution is poured into diisopropyl ether. The precipitate obtained is collected by filtration, added to a mixture of tetrahydrofuran, ethyl acetate and water and the pH is adjusted to 7.2 with aqueous sodium bicarbonate. The separated aqueous layer is washed with ethyl acetate and adjusted to pH 3.0 with 1N hydrochloric acid and washed with tetrahydrofuran. The tetrahydrofuran solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on HP-20 (eluent: 20% isopropanol-water).

The desired portion is evaporated under reduced pressure. Ethyl acetate is added to the aqueous layer and the mixture is adjusted to pH 2.8 with 1N hydrochloric acid. The extracted ethyl acetate solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the obtained crystals were collected by filtration to obtain 7β- (2-phenylacetamido) -3- (5-aminothiazol-2-yl) thio-3-cepem-4-carboxylic acid (194 mg ).

IR (KBr): 1774, 1678, 1656, 1515 cm ^-1

NMR (DMSO-d ₆ , δ): 3.41 (2H, s), 3.51 (2H, d, J = 3.8 Hz), 5.13 (1H, d, J = 4.7 Hz), 5.62 (1H, dd, J = 4.7 Hz and 8.3 Hz), 6.84 (1H, s), 7.1-7.4 (7H, m), 9.09 (1H, d, J = 8.3 Hz)

FAB-MASS (m / z): 449 (M + H) ⁺

Example 95

Potassium at -10 ° C. in a solution of 4-carboxymethyl-2-mercapto-4,5,6,7-tetrahydrobenzothiazole (780 mg) in tetrahydrofuran (11.7 mL) and dimethoxyethane (11.7 mL) t-butoxide (667 mg) is added and the solution is stirred at the same temperature for 20 minutes. On the other hand, benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cepem-4-carboxylate (1.64) in tetrahydrofuran (8.2 mL) and dimethoxyethane (8.2 mL) g) is added to the solution at -15 ° C. After stirring for 2 hours under ice cooling, the solution is poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to potassium benzhydryl 7β- (2-phenylacetamido) -3- (4-carboxymethyl-4,5,6, 7-tetrahydrobenzothiazol-2-yl) thio-3-cepem-4-carboxylate (2.02 g) is obtained.

NMR (DMSO-d ₆ , δ): 1.4-2.1 (4H, m), 2.1-2.5 (1H, m), 2.6-2.8 (2H, m), 2.80-3.0 (1H, m), 3.0-3.3 ( 1H, m), 3.4-3.8 (4H, m), 5.1-5.4 (1H, m), 5.7-5.9 (1H, m), 6.8-7.0 (1H, m), 7.1-7.5 (15H, m), 9.2-9.3 (1 H, m)

FAB-MASS (m / z): 750 (M + H) ⁺

Example 96

To a solution of 4- (2-carboxyethyl) -2-mercaptothiazole (972 mg) in tetrahydrofuran (14.6 mL) and dimethoxyethane (14.6 mL) was added potassium t-butoxide (960 mg) at -10 ° C. And the mixture is stirred at the same temperature for 20 minutes. On the other hand, benzhydryl 7β- [2- (3-thienyl) acetamido] -3-methanesulfonyloxy-3-cepem-4-carboxylate (2.5 g) in tetrahydrofuran (35 ml) was Add to the solution at 15 ° C. After stirring for 2 hours under ice cooling, the solution is poured into a mixture of water and ethyl acetate. The separated organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Diisopropyl ether was added to the residue and the obtained precipitate was collected by filtration to collect potassium benzhydryl 7β-[(2- (3-thienyl) acetamido) -3- [4- (2-carboxyethyl) thia Zol-2-yl] thio-3-cepem-4-carboxylate (2.69 g) is obtained.

NMR (DMSO-d ₆ , δ): 2.61 (2H, t, J = 7.7 Hz), 2.89 (2H, t, J = 7.8 Hz), 3.57 (2H, s), 3.50 and 3.77 (2H, ABq, J = 17.7 Hz), 5.27 (1H, d, J = 4.9 Hz), 5.82 (1H, dd, J = 4.9 Hz and 7.7 Hz), 6.97 (1H, s), 7.1-7.6 (14H, m), 9.21 ( 1H, d, J = 7.7 Hz)

FAB-MASS (m / z): 716 (M + H) ⁺

Example 97

N- to a solution of benzhydryl 7β-amino-3-[(Z) -2- (3-pyridyl) vinylthio] -3-cepem-4-carboxylate (500 mg) in tetrahydrofuran (12.5 mL) Trimethylsilylacetamide (550 mg) is added and stirred at room temperature for 20 minutes. To the solution is added a solution of the above phenyl acetyl chloride (146 μl) at −20 ° C. for 2 minutes. The mixture is stirred at -20 to -15 ° C for 50 minutes. To the reaction mixture is added water (50 mL), ethyl acetate (50 mL) and tetrahydrofuran (15 mL). The organic layer is separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give benzhydryl 7β- (2-phenylacetamido) -3-[(Z) -2- (3-pyridyl) vinylthio] -3-cepem-4-carboxylate (532 mg ).

NMR (DMSO-d ₆ , δ): 3.50 and 3.59 (2H, ABq, J = 14 Hz), 3.82 and 4.10 (2H, ABq, J = 18 Hz), 5.21 (1H, d, J = 5 Hz), 5.78 (1H , dd, J = 5Hz and 8Hz), 6.76 (1H, d, J = 11Hz), 6.81 (1H, d, J = 11Hz), 6.94 (1H, s), 7.2-7.5 (16H, m), 7.7- 7.8 (1H, m), 8.4-8.5 (1H, m), 8.59 (1H, m), 9.22 (1H, d, J = 8 Hz)

APCI-MASS (m / z): 620 (M + H) ⁺

Example 98

N- to a solution of benzhydryl 7β-amino-3-[(E) -2- (4-pyrazole) vinylthio] -3-cepem-4-carboxylate (515 mg) in tetrahydrofuran (12.5 mL) Trimethylsilylacetamide (550 mg) is added and stirred at room temperature for 15 minutes. To the solution is added dropwise a solution of phenylacetylchloride (146 μL) for 20 minutes at −20 ° C. The mixture is stirred at -20 to -15 ° C for 1 hour. To the reaction mixture is added water (100 mL) and ethyl acetate (100 mL). The organic layer is separated with buffer (pH 7) and saturated aqueous sodium chloride solution, washed, dried over magnesium sulfate and concentrated in vacuo. The residue was separated by column chromatography on silica gel (eluent; dichloromethane: acetate = 9: 1) to give benzhydryl 7β- (2-phenylacetamido) -3-[(E) -2- (1-benzyl Carbonyl-pyrazol-4-yl) vinylthio] -3-cepem-4-carboxylate (93.4 mg) is obtained.

NMR (DMSO-d ₆ , δ): 3.51 and 3.60 (2H, ABq, J = 14 Hz), 3.80 and 3.99 (2H, ABq, J = 18 Hz), 4.45 (2H, S), 5.21 (1H, d, J = 5 Hz), 5.72 (1H, dd, J = 5 and 8 Hz), 6.74 (1H, d, J = 15 Hz), 6.90 (1H, s), 7.18 (1H, d, J = 15 Hz), 7.2-7.6 ( 15H, m), 8.20 (1H, s), 8.55 (1H, s), 9.19 (1H, d, J = 8 Hz)

APCI-MASS (m / z): 609 (M + H) ⁺

Example 99

Benzhydryl 7β- (2-phenylacetamido) -3-cepem-4-carboxylate in tetrahydrofuran (20 ml), dimethoxyethane (2.0 g) and N, N-dimethylformamide (20 mg) To a solution of 2.0 g) is added 1-carboxymethyl-5-mercapto-1,2,3,4-tetrazol dipotassium salt (608 mg) with stirring at -25 ° C. The mixture is stirred for 30 minutes at -25 to -15 ° C and for 2 hours at -15 to -8 ° C. The reaction mixture is added with stirring to a mixture of ethyl acetate (100 mL) and ice water (100 mL). Ethyl acetate (150 mL) is added to the separated aqueous solution. The mixture is adjusted to pH 1.8 with 1N hydrochloric acid. The organic layer is separated, washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to yield benzhydryl 7β- (2-phenylacetamido) -3- (1-carboxymethyl-1,2,3,4-tetrazol-5-yl) thio-3-cepem 4--4-carboxylate (412 mg) is obtained.

NMR (DMSO-d ₆ , δ): 3.3-3.7 (4H, m), 5.2-5.5 (2H, m), 5.24 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 Hz and 8 Hz ), 6.95 (1H, s), 7.2-7.5 (15H, m), 9.19 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 643.1

Example 100

Benzhydryl 7β- (2-phenylacetamido) -3- [2- (3-pyridyl) ethylthio] -3-cefem in a mixture of dichloromethane (1.8 mL) and anisol (0.6 mL) To a solution of -4-carboxylate (632 mg) is added trifluoroacetic acid (1.2 mL) under ice cooling. The mixture is stirred at the same temperature for 1 hour 30 minutes. The mixture is poured into diisopropyl ether (60 mL) and the resulting veterans are collected by filtration and dried under vacuum. The precipitate is dissolved in a mixture of aqueous sodium hydrogen carbonate solution (188 mg / 50 mL), tetrahydrofuran (20 mL) and ethyl acetate (40 mL). Tetrahydrofuran (20 ml) and ethyl acetate (40 ml) are added to the separated aqueous layer and the pH is adjusted to 3.0 with 1 N hydrochloric acid. The precipitate obtained was collected by filtration, washed with water, ethyl acetate and n-hexane and dried to 7β- (2-phenylacetamido) -3- [2- (3-pyridyl) ethylthio] -3 Obtain cefe-4-carboxylic acid (366 mg).

NMR (DMSO-d ₆ , δ): 2.7-2.9 (2H, m), 3.0-3.2 (2H, m), 3.49 and 3.58 (2H, ABq, J = 14 Hz), 3.75 and 3.85 (2H, ABq, J = 17 Hz), 5.11 (1H, d, J = 5 Hz), 5.62 (1H, d, J = 5 Hz and 8 Hz), 7.2-7.4 (6H, m), 7.6-7.8 (1H, m), 8.4-8.5 ( 2H, m), 9.13 (1H, d, J = 8 Hz)

FAB-MASS (m / z): 456.0

Example 101

Benzhydryl 7β- (2-phenylacetamido) -3- [4-carbamoylmethylthiazol-2-yl) thiomethylthio in a mixture of dichloromethane (0.4 mL) and anisol (0.125 mL) To a solution of] -3-cefe-4-carboxylate (125 mg) is added trifluoroacetic acid (0.25 mL) under ice cooling. The mixture is stirred at the same temperature for 1 hour. The reaction mixture was poured into diisopropyl ether (50 mL) and the obtained precipitate was collected by filtration to collect 7β- (2-phenylacetamido) -3- [4-carbamoylmethylthiazol-2-yl) thiomethyl Thio] -3-cepem-4-carboxylic acid (89.0 mg) is obtained.

NMR (DMSO-d ₆ , δ): 3.4-3.6 (6H, m), 3.40 and 3.76 (2H, ABq, J = 18 Hz), 5.20 (1H, d, J = 5 Hz), 5.74 (1H, dd, J = 5 Hz and 8 Hz), 6.99 (1H, br s), 7.1-7.3 (5H, m), 7.4 (1H, br s), 7.53 (1H, s), 9.22 (1H, d, J = 8 Hz)

Example 102

7β- (2-phenylacetamido) -3- [4- (carbamoylmethylthiazol-2-yl) thio] -3-cepem-4-carboxylic acid (1.84 g), water (18 ml) and acetone (10 Ml) is added and dissolved in sodium acetate (924 mg). The solution is stirred at room temperature for 1 hour. The obtained precipitate was collected by filtration to give 7β- (2-phenylacetamido) -3- [4-carbamoylmethylthiazol-2-yl) thio] -3-cepem-4-carboxylate (890 mg). do.

IR (new sol): 3250, 1750, 1650, 1605, 1530, 1350, 1260cm ^-1

NMR (D ₂ O, δ): 3.40 and 3.76 (2H, ABq, J = 17 Hz), 3.6-3.8 (4H, m), 5.19 (1H, d, J = 5 Hz), 5.68 (1H, d, J = 5 Hz), 7.3-7.5 (6 H, m)

FAB-MASS (m / z): 512.6

Example 103

7β- (2-phenylacetamido) -3- [4-carboxymethylthiazol-2-yl) thio] -3-cepem-4-carboxylic acid in tetrahydrofuran (37 mL) and methanol (20 mL) To 950 mg) is added sodium acetate (317 mg) in methanol (20 mL). The mixture is stirred at room temperature for 20 minutes. The precipitate obtained was collected by filtration, washed successively with methanol and n-hexane and dried under vacuum to give sodium 7β- (2-phenylacetamido) -3- [4-carboxymethyl-thiazol-2-yl) Thio] -3-cepem-4-carboxylate (0.77 g) is obtained.

IR (KBr): 3400, 3330, 1770, 1710, 1650, 1600, 1580, 1530, 1390, 1350, 1260, 1220cm ^-1

NMR (D ₂ O, δ): 3.42 and 3.75 (2H, ABq, J = 18 Hz), 3.6-3.8 (4H, m), 5.19 (1H, d, J = 5 Hz), 5.67 (1H, d, J = 5 Hz), 7.3-7.5 (6 H, m)

FAB-MASS (m / z): 535.9

Example 104

To a solution of 2-mercapto-5-methyl-1,3,4-thiadiazole (142 mg) in dimethoxyethane (3 mL) was added potassium t-butoxide (120 mg) with stirring at −20 ° C., The mixture is stirred at -20 to -10 &lt; 0 &gt; C for 30 minutes to obtain a potassium salt solution. Meanwhile, a solution of 7β- (2-phenylacetamido) -3-trifluoromethanesulfonyloxy-3-cepem-4-carboxylic acid (500 mg) in dimethoxyethane (4 mL) and dichloromethane (7.5 mL) To this is added N-trimethylsilylacetamide (562 mg). The suspension is stirred for 30 minutes at room temperature. To the mixture is added the potassium salt solution prepared above at -20 ° C and the mixture is stirred at -20 to -10 ° C for 30 minutes and at 0 to 5 ° C for 1 hour and 30 minutes. The mixture is poured into a mixture of ice water (20 mL) and ethyl acetate (30 mL). The organic layer is separated and water (20 ml) is added. The mixture is adjusted to pH 6.8 with 1N sodium hydroxide solution. The aqueous layer is separated and evaporated in vacuo to remove organic solvent. The obtained residue is purified by high performance liquid chromatography (HPLC) (R-ODS-C-15, YMC-pack), eluting with 27% acetonitrile-phosphate buffer (pH 3.0). The solution is extracted with ethyl acetate (100 mL). The extract is concentrated in vacuo. The residue is dissolved in acetonitrile (60 mL) and water (20 mL). The solution is concentrated in vacuo. The residue was triturated with water to give 7β- (2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid (262 mg). To obtain.

NMR (DMSO-d ₆ , δ): 2.72 (3H, s), 3.48 and 3.57 (2H, ABq, J = 14 Hz), 3.53 and 3.85 (2H, ABq, J = 18 Hz), 5.21 (1H, d, J = 5 Hz), 5.78 (1H, dd, J = 5 Hz and 8 Hz), 7.2-7.4 (5H, m), 9.23 (1H, d, J = 8 Hz)

Example 105

7β- (2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cepem- in N, N-dimethylacetamide (4 mL) Cesium carbonate (200 mg) is added to a solution of 4-carboxylic acid (492 mg) under ice-cooling and stirred at the same temperature for 1 hour 30 minutes. Iodomethyl pivalate (297 mg) is added to the mixture and stirred at the same temperature for 1 hour. To the mixture is added water (50 mL) and ethyl acetate (50 mL). The organic layer is separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give pivaloyloxymethyl 7β- (2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cepem 4--4-carboxylate (492 mg) is obtained.

NMR (CDCl ₃ , δ): 1.21 (9H, s), 2.78 (3H, s), 3.46 and 3.75 (2H, ABq, J = 18 Hz), 3.60 and 3.69 (2H, ABq, J = 16 Hz), 5.01 ( 1H, d, J = 5 Hz), 5.8-6.0 (3H, m), 6.12 (1H, d, J = 9 Hz), 7.2-7.4 (5H, m)

FAB-MASS (m / z): 563.0

Example 106

Benzhydryl 7β- [2- (2-aminothiazol-4-yl) -acetamido] -3 in a mixture of tetrahydrofuran (15 mL) and N, N-dimethylacetamide (5 mL) To a solution of-(5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid (1.0 g) under ice cooling with acetyl chloride (245 μL) and pyridine (254 μL) Add. The mixture is stirred at the same temperature for 4 hours. The reaction mixture is added to a mixture of ethyl acetate (70 mL) and ice water (50 mL). The organic layer is separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give benzhydryl 7β- [2- (2-acetylaminothiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazole-2 -Yl) thio-3-cepem-4-carboxylate (675 mg) is obtained.

NMR (DMSO-d ₆ , δ): 2.11 (3H, s), 2.71 (3H, s), 3.58 and 3.87 (2H, ABq, J = 17 Hz), 3.59 (2H, s), 5.28 (1H, d, J = 5 Hz), 5.87 (1H, dd, J = 5 Hz and 8 Hz), 6.87 (1H, s), 6.97 (1H, s), 7.2-7.4 (10H, m), 9.14 (1H, d, J = 8 Hz ), 12.09 (1H, s)

FAB-MASS (m / z): 679.1

Example 107

7β- [2- (5-chloro-2-formylaminothiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio- To a suspension of 3-cefe-4-carboxylic acid (380 mg), methanol (4 mL) and tetrahydrofuran (4 mL) is added concentrated hydrochloric acid (153 μL). The reaction mixture is added to a mixture of ethyl acetate (20 mL) and ice water (50 mL). Ethyl acetate (20 mL) is added to the aqueous solution. The mixture is adjusted to pH 7 with 1N hydrochloric acid. To the separated aqueous solution is added ethyl acetate (20 mL). The mixture is adjusted to pH 2 with 1N hydrochloric acid. The precipitate was collected by filtration, washed with ethyl acetate and dried to give 7β- [2- (2-amino-5-chlorothiazol-4-yl) acetamido] -3- (5-methyl-1,3, Obtain 4-thiadiazol-2-yl) thio-3-cepem-4-carboxylic acid (188 mg).

NMR (DMSO-d ₆ , δ): 2.72 (3H, s), 3.38 (2H, s), 3.53 and 3.85 (2H, ABq, J = 18 Hz), 5.23 (1H, d, J = 5 Hz), 5.78 ( 1H, dd, J = 5 Hz and 8 Hz), 7.16 (2H, br s), 9.06 (1H, d, J = 8 Hz)

Example 108

To a solution of 4- (2-mercaptothiazol-4-yl) benzoic acid (980 mg) in tetrahydrofuran (13.7 mL) and dimethoxyethane (13.7 mL) was added potassium t-butoxide (642 mg) at -10 ° C. And the solution is stirred at the same temperature for 20 minutes. Meanwhile, a solution of benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cepem-4-carboxylic acid (1.8 g) in tetrahydrofuran (20 mL) was described above at -15 ° C. To the solution. After stirring for 2 hours and 30 minutes under ice cooling, the solution is poured into a mixture of water (70 mL) and ethyl acetate (70 mL) and the pH is adjusted to 7.0 with 1N hydrochloric acid. The separated organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is separated by column chromatography on silica gel, eluting with a mixture of ethyl acetate and methanol (4.5: 1). The moieties containing the desired compound are combined and evaporated in vacuo to form benzhydryl 7β- (2-phenylacetamido) -3- [4- (4-carboxyphenyl) thiadiazol-2-yl] thio-3- Cefem-4-carboxylate (465 mg) is obtained.

IR (KBr): 1787, 1739, 1685, 1409, 1375, 1224cm ^-1

NMR (DMSO-d ₆ , δ): 3.56 (2H, br s), 3.68 and 3.92 (2H, ABq, J = 17.7 Hz), 5.30 (1H, d, J = 5.0 Hz), 5.86 (1H, dd, J = 5.0 Hz and 8.3 Hz), 6.98 (1H, s), 7.15-7.50 (15H, m), 7.85-8.15 (4H, m), 8.30 (1H, s), 9.28 (1H, d, J = 8.3 Hz)

Example 109

Potassium Benzhydryl 7β- (2-phenylacetamido) -3- [4- (4-carboxyphenyl) thiazol-2-yl] thio] -3-cepem-4-carboxylate (450 mg), anisol To a mixture of (0.45 mL) and dichloromethane (1.35 mL) is added trifluoroacetic acid (0.9 mL) at 15 ° C. After stirring for 1 hour and 30 minutes at room temperature, the solution is poured into diisopropyl ether. The obtained precipitate was collected by filtration and added to a mixture of tetrahydrofuran (10 mL) and water (15 mL), and the solution was adjusted to pH 7.2 with sodium hydrogen carbonate. The separated aqueous solution was adjusted to pH 3.0 with 1N hydrochloric acid and extracted with tetrahydrofuran. The tetrahydrofuran solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue and the powder obtained was collected by filtration and dried under vacuum to afford 7β- (2-phenylacetamido) -3- [4- (4-carboxyphenyl) thiazol-2-yl] thio- Obtain 3-cepm-4-carboxylic acid (75 mg).

IR (KBr): 1776, 1685, 1660, 1610, 1351, 1247 cm ^-1

NMR (DMSO-d ₆ , δ): 3.53 (2H, dd, J = 13.9 Hz and 18.6 Hz), 3.62 and 3.90 (2H, ABq, J = 17.7 Hz), 5.26 (1H, d, J = 5.0 Hz) , 5.77 (1H, dd, J = 5.0 Hz and 8.3 Hz), 7.15-7.35 (5H, m), 8.04 (4H, dd, J = 8.7 Hz and 13.3 Hz), 8.40 (1H, s), 9.23 (1H , d, J = 8.3 Hz)

FAB-MASS (m / z): 554 (M + H) ⁺

Example 110

Sodium 7β- [2- (2-thienyl) acetamido) -3- [4- (2-carboxyethyl) thiadiazol-2-yl] thio-3-cepem-4-carboxylate

IR (KBr): 1778, 1658, 1527, 1388, 1249 cm ^-1

NMR (DMSO-d ₆ , δ): 2.50-2.65 (2H, m), 2.80-2.95 (2H, m), 3.26 and 3.70 (2H, ABq, J = 16.8 Hz), 3.76 (2H, s), 5.08 (1H, d, J = 4.9 Hz), 5.56 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.85-7.00 (2H, m), 7.24 (1H, s), 7.30-7.40 (1H, m) , 9.17 (1H, d, J = 8.4 Hz)

Example 111

7β- [2- (2-thienyl) acetamido] -3- [4- (2-carboxyethyl) thiadiazol-2-yl] thio-3-cepem-4-carboxylic acid in water (50 mL) To (100 mg) of solution is added 0.1 mol / L sodium hydroxide solution (3.9 mL). The solution was lyophilized to disodium 7β- [2- (2-thienyl) acetamido) -3- [4- (2-carboxyethyl) thiadiazol-2-yl] thio-3-cepem-4- Obtained carboxylate (108.3 mg).

IR (KBr): 1766, 1662, 1612, 1552, 1348, 1238cm ^-1

NMR (DMSO-d ₆ , δ): 2.10-2.30 (2H, m), 2.70-2.90 (2H, m), 3.27 and 3.70 (2H, ABq, J = 16.8 Hz), 3.76 (2H, s), 5.08 (1H, d, J = 5.0 Hz), 5.56 (1H, dd, J = 5.0 Hz and 8.4 Hz), 6.90-7.0 (2H, m), 7.15 (1H, s), 7.30-7.40 (1H, m) , 9.20 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 534 (M + H) ⁺

Example 112

0.1 mol / l in 7β- (2-phenylacetamide) -3- (4-carboxymethylthiazol-2-yl) thiadiazole-3-cefe-4-carboxylic acid (100 mg) in water (50 mL). Sodium hydroxide solution (4.06 mL) is added. Lyophilize the solution. The powder obtained was dissolved in a mixture of methanol (0.5 mL) and acetone (1.3 mL) with stirring at 30 ° C. Stirring was continued for 2 hours at room temperature to obtain crystals which were collected by filtration and dried to 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3- Cefem-4-carboxylate (69.1 mg) is obtained.

IR (KBr): 1753, 1656, 1623, 1535, 1390, 1261 cm ^-1

NMR (DMSO-d ₆ , δ): 3.25 and 3.71 (2H, ABq, J = 17.0 Hz), 3.53 (2H, dd, J = 14 Hz and 17.0 Hz), 3.65 (2H, s), 5.05 (1H, d , J = 5.0 Hz), 5.54 (1H, dd, J = 5.0 Hz and 8.4 Hz), 7.05-7.35 (5H, m), 7.37 (1H, s), 9.15 (1H, d, J = 8.4 Hz)

FAB-MASS (m / z): 536 (M + H) ⁺

Claims (22)

A cefem compound of formula (I) or salt thereof Formula I In Formula I, R ¹ is aryl (lower) alkyl which may have 1 to 3 suitable substituents selected from the group consisting of lower alkyl, hydroxy and halogen which may form a ring with the carbon atom to which it is attached; Heterocyclic (lower) alkyl or cyano (lower) alkenylthio (lower) alkyl which may have from 1 to 3 suitable substituents selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and protected amino ego, R ² contains acyl (lower) alkyl, hydroxy (lower) alkyl, mono or di (lower) alkylamino (lower) alkyl, amino (lower) alkyl, protected amino (lower) alkyl, acyl, acylamino and carboxy Heterocyclic groups having 1 to 3 suitable substituents selected from the group consisting of aryl, wherein the heterocyclic group may further have lower alkyl; Pyridyl (lower) alkyl; Pyrazolylethyl, which may have aryl (lower) alkyl; Thiadiazolyl (lower) alkyl; 5-aminothiazolyl; Thiadiazolyl with (lower) alkyl; Heterocyclic (lower) alkenyl which may have 1 to 3 suitable substituents or heterocyclicthio (lower) alkyl which may have 1 to 3 suitable substituents, R ³ is carboxy or protected carboxy, Provided that when R ¹ is aryl (lower) alkyl and R ² is thiadiazolyl having lower alkyl, then R ³ is acyloxy (lower) alkoxycarbonyl, 2) when R ¹ is aryl (lower) alkyl with halogen, R ² is not thiadiazolyl with lower alkyl, 3) When R ¹ is aminothiazolyl (lower) alkyl, R ² is not thiadiazolyl with lower alkyl. The method of claim 1, Phenyl (lower) alkyl which may have 1 to 3 suitable substituents selected from the group consisting of lower alkyl, hydroxy and halogen which may form a 3-6 membered ring with the carbon atom to which R ¹ is bonded; Thienyl (lower) alkyl, thiazolyl (lower) alkyl or thiadiazolyl (lower) alkyl [these each having 1 to 3 suitable substituents selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and acylamino Or cyano (lower) alkenylthio (lower) alkyl, Thiazolyl wherein R ² has 1 to 3 suitable substituents selected from the group consisting of acyl (lower) alkyl, hydroxy (lower) alkyl, acyl, acylamino and carboxy-containing phenyl, wherein thiazolyl further comprises lower alkyl May have); 1 to 3 selected from the group consisting of lower alkyl, hydroxy (lower) alkyl, mono or di (lower) alkylamino (lower) alkyl, amino (lower) alkyl, acylamino (lower) alkyl and acyl (lower) alkyl Thiadiazolyl with suitable substituents; 4,5,6,7-tetrahydrobenzothiazolyl with acyl (lower) alkyl; Pyridyl (lower) alkyl; Pyrazolylethyl, which may have triphenyl (lower) alkyl; Thiadiazolyl (lower) alkyl; 5-aminothiazolyl; Triazolyl with acyl (lower) alkyl; Tetrazolyl with acyl (lower) alkyl; Pyridyl (lower) alkenyl; Pyrazolyl (lower) alkenyl which may have an acyl; Or thiazolyl (lower) alkylthio which may have an acyl (lower) alkyl, R ³ is carboxy or protected carboxy, Provided that when R ¹ is phenyl (lower) alkyl and R ² is thiadiazolyl having lower alkyl, then R ³ is acyloxy (lower) alkoxycarbonyl, 2) when R ¹ is phenyl (lower) alkyl with halogen, R ² is not thiadiazole with alkyl, and 3) when R ¹ is aminothiazolyl (lower) alkyl, R ² is thia with alkyl Non-diazolyl compounds. 3. A compound according to claim 2, wherein R ¹ is phenyl (lower) alkyl or thienyl (lower) alkyl and R ² is thiazolyl with carboxy (lower) alkyl, thiazolyl with carbamoyl (lower) alkyl or N, N A thiazolyl having a di (lower) alkylcarbamoyl (lower) alkyl and R ³ is carboxy. 4. The compound of claim 3, wherein R ¹ is phenyl (lower) alkyl, R ² is thiazolyl with carboxy (lower) alkyl, and R ³ is carboxy. 4. A compound according to claim 3, wherein R ¹ is phenyl (lower) alkyl, R ² is thiazolyl with carbamoyl (lower) alkyl, and R ³ is carboxy. The compound of claim 3, wherein R ¹ is thienyl (lower) alkyl, R ² is thiazolyl with carboxy (lower) alkyl or thiazolyl with carbamoyl (lower) alkyl, and R ³ is carboxy. The compound according to claim 4, which is 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazolyl) thio-3-cepem-4-carboxylic acid. 6. A compound according to claim 5, which is 7β- (2-phenylacetamido) -3- (4-carboxymoylmethylthiazolyl) thio-3-cepem-4-carboxylic acid. 7β- [2- (3-thienyl) acetamido] -3- (4-carboxymethylthiazolyl) thio-3-cepem-4-carboxylic acid, 7β- [2- (2- Thienyl) acetamido] -3- [4- (2-carboxyethyl) -thiazolyl] thio-3-cepem-4-carboxylic acid or 7β- [2- (3-thienyl) acetamido] -3 -(4-carbamoylmethylthiazolyl) thio-3-cepem-4-carboxylic acid. (i) reacting a compound of formula II or a salt thereof with a compound of formula III or a salt thereof (ii) removing the carboxy protecting group from a compound of formula (Ia) or a salt thereof to obtain a compound of formula (Ib) or a salt thereof, or (ii) reacting a compound of formula IV or a reactive derivative thereof or a salt thereof in an amino group with a compound of formula V or a reactive derivative thereof or a salt thereof in a carboxy group, or (iv) A process for preparing the compound of formula (I) or a salt thereof, comprising protecting the carboxy from a compound of formula (Ib) or a reactive derivative thereof or a salt thereof in a carboxy group to obtain a compound of formula (Ia). HS-R ² R ¹ -COOH In Chemical Formulas II, III, Ia, Ib, IV, and V, R ¹ , R ² and R ³ are defined in claim 1, R ⁴ is a leaving group, R ⁵ is protected carboxy. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or excipient. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. A compound of claim 1, or a pharmaceutically acceptable salt thereof, for use as a medicament. A method of preventing and / or treating a disease caused by a Helicobacter pylori infection comprising administering to the human or animal the cefem compound of claim 1 or a pharmaceutically acceptable salt thereof. A cefe compound (I) or a pharmaceutically acceptable salt thereof and acid secretion inhibitor of claim 1 for use simultaneously, separately or continuously to prevent and / or treat a disease caused by a Helicobacter pylori infection. Complex formulation products. The cefem compound (I) of claim 1, or a pharmaceutically acceptable salt thereof, for adjuvant treatment of a disease caused by a Helicobacter pylori infection in combination with an acid secretion inhibitor. The cefem compound (I) of claim 1 or a pharmaceutically acceptable salt and acid secretion thereof for the manufacture of a medicament which is used simultaneously, individually or continuously to prevent and / or treat a disease caused by a Helicobacter pylori infection. Use of inhibitors. A product comprising the cefem compound (I) of claim 1 and an acid secretion inhibitor for use simultaneously, separately or continuously as a medicament. A pharmaceutical composition comprising the cefem compound (I) of claim 1 and an acid secretion inhibitor and any pharmaceutically acceptable carrier or excipient. A product comprising the cefem compound (I) of claim 1 or a pharmaceutically acceptable salt thereof (a) and an acid secretion inhibitor (b) in a weight ratio of 0.01 / 1 to 100/1. A method of treating or inhibiting a disease caused by Helicobacter pylori infection, comprising administering an effective amount of the cefem compound of claim 1 to a patient in need of treating or inhibiting a disease caused by Helicobacter pylori infection. The patient of claim 21, wherein the cefe compound (I) of claim 1 is combined with the acid secretion inhibitor with a weight ratio of the acid secretion inhibitor to the cefe compound (I) of claim 1 in the range of 0.01 / 1 to 100/1. Administered to.